TY - JOUR AB - An animal's metabolic state strongly influences its behavior. Hungry animals prioritize food-seeking and feeding behaviors, while sated animals suppress these behaviors to engage in other activities. Additionally, neuronal activity and synaptic transmission are among the most energy-expensive processes. However, neurons do not uptake nutrients from the circulation. Instead, glia fulfill this highly evolutionarily conserved function in addition to modulating neuronal activity and behavior. However, how different glia subtypes sense metabolic state and modulate behavior is incompletely understood. Here, we unravel two types of glia-mediated modulation of metabolic-state-dependent behavior. In food-deprived flies, astrocyte-like and perineurial glia promote foraging and feeding, respectively, while cortex glia suppress these behaviors. We further show that adenosine and adenosine receptors modulate intracellular calcium levels in these glia subtypes, which ultimately controls behavior. This study reveals a mechanism of how different glia subtypes sense an animal's metabolic state and modulate its behavior accordingly. AU - De Backer, J.F.* AU - Karges, T.* AU - Papst, J.* AU - Pınar, Z.N.* AU - Coman, C.* AU - Ahrends, R.* AU - Xu, Y. AU - García-Cáceres, C. AU - Grunwald Kadow, I.C.* C1 - 74838 C2 - 57625 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Adenosine signaling in glia modulates metabolic state-dependent behavior in Drosophila. JO - Cell Rep. VL - 44 IS - 6 PB - Cell Press PY - 2025 SN - 2211-1247 ER - TY - JOUR AB - In the Drosophila female germline, oskar messenger RNA is transported on microtubules from the nurse cells to the posterior pole of the oocyte, where it is translated. Transport of oskar transcripts from the nurse cells into the oocyte requires dynein, while localization of the mRNAs within the oocyte to the posterior pole is dependent upon kinesin-1. Staufen, a double-stranded RNA (dsRNA)-binding protein, has been shown to bind the oskar mRNA transport complex in the oocyte and inactivate dynein; however, it remains unclear how kinesin is activated. Here, using surface plasmon resonance, nuclear magnetic resonance spectroscopy, and RNA imaging within egg chambers, we demonstrate that Staufen directly interacts with Tropomyosin1-I/C (Tm1), a non-canonical kinesin adaptor. This work provides molecular evidence of how Staufen integrates into the oskar messenger ribonucleoprotein (mRNP) complex. AU - Gaber, T.* AU - Monecke, T.* AU - Grabowski, J.* AU - Simon, B.* AU - Williams, T.* AU - Roman, V. AU - Chao, J.* AU - Hennig, J.* AU - Ephrussi, A.* AU - Niessing, D. AU - Heber, S.D.* C1 - 75025 C2 - 57709 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - A direct interaction between the RNA-binding proteins Staufen and Tm1-I/C in the oskar mRNA transport complex. JO - Cell Rep. VL - 44 IS - 7 PB - Cell Press PY - 2025 SN - 2211-1247 ER - TY - JOUR AB - Genetic variants in TMEM106B, coding for a transmembrane protein of unknown function, have been identified as critical genetic modulators in various neurodegenerative diseases with a strong effect in patients with frontotemporal degeneration. The luminal domain of TMEM106B can form amyloid-like fibrils upon proteolysis. Whether this luminal domain is generated under physiological conditions and which protease(s) are involved in shedding remain unclear. We developed a commercially available antibody against the luminal domain of TMEM106B, allowing a detailed survey of the proteolytic processing under physiological conditions in cellular models and TMEM106B-related mouse models. Moreover, fibrillary TMEM106B was detected in human autopsy material. We find that the luminal domain is generated by multiple lysosomal cysteine-type proteases. Cysteine-type proteases perform additional C-terminal trimming, for which experimental evidence has been lacking. The presented results allow an in-depth perception of the processing of TMEM106B, a prerequisite to understanding factors leading to fibril formation. AU - Held, S.* AU - Erck, C.* AU - Kemppainen, S.* AU - Bleibaum, F.* AU - Giridhar, N.J.* AU - Feederle, R. AU - Krenner, C.* AU - Juopperi, S.P.* AU - Calliari, A.* AU - Mentrup, T.* AU - Schröder, B.* AU - Dickson, D.W.* AU - Rauramaa, T.* AU - Petrucelli, L.* AU - Prudêncio, M.I.* AU - Hiltunen, M.* AU - Lüningschrör, P.* AU - Capell, A.* AU - Damme, M.* C1 - 72882 C2 - 56771 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Physiological shedding and C-terminal proteolytic processing of TMEM106B. JO - Cell Rep. VL - 44 IS - 1 PB - Cell Press PY - 2025 SN - 2211-1247 ER - TY - JOUR AB - Virus-infected cells often exhibit dramatic cellular changes accompanied by altered mitochondrial function. The contribution of factors shaping the inner mitochondrial membrane (IMM) and cristae architecture to viral replication is insufficiently understood. Single-cell transcriptomics applying vesicular stomatitis virus infection suggests involvement of factors determining IMM architecture following infection. Consistently, inhibition of the F1FO adenosine triphosphate (ATP) synthase reduces viral replication, which is associated with oligomerization of this complex and altered IMM structure. Moreover, deletion of mitochondrial contact site and cristae organizing system (MICOS) complex by targeting MIC60 results in reduced viral replication. Generation of Mic60inv/invCD11c-Cre+ mice uncovers reduced crista junctions and viral replication in bone marrow-derived dendritic cells. Consequently, reduced viral replication in CD11c-expressing cells limits prolonged immune activation. Altogether, by linking the F1FO ATP synthase and the MICOS complex to viral replication and immune activation, we describe links between the mitochondrial structure-metabolism and the immune response against viral infection. AU - Katahira, I.* AU - Liebrand, N.* AU - Gorzkiewicz, M.* AU - Klahm, N.P.* AU - Abromavičiūtė, D.* AU - Werner, J.* AU - Krings, K.S.* AU - Orywol, S.* AU - Lautwein, T.* AU - Köhrer, K.* AU - Herebian, D.* AU - Mayatepek, E.* AU - Anstötz, M.* AU - Bergmann, A.K.* AU - Kondadi, A.K.* AU - Xu, H.C.* AU - Pandyra, A.A.* AU - Kobayashi, T.* AU - Brenner, D.* AU - Floss, T. AU - Kalinke, U.* AU - Reichert, A.S.* AU - Lang, P.A.* C1 - 75112 C2 - 57818 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Controlling mitochondrial membrane architecture via MIC60 determines viral replication to promote anti-viral immunity. JO - Cell Rep. VL - 44 IS - 7 PB - Cell Press PY - 2025 SN - 2211-1247 ER - TY - JOUR AB - Intermittent fasting (IF) is a nutritional lifestyle intervention with broad metabolic benefits, but whether the impact of IF depends on the individual's age is unclear. Here, we investigated the effects of IF on systemic metabolism and β cell function in old, middle-aged, and young mice. Short-term IF improves glucose homeostasis across all age groups without altering islet function and morphology. In contrast, while chronic IF is beneficial for adult mice, it results in impaired β cell function in the young. Using single-cell RNA sequencing (scRNA-seq), we delineate that the β cell maturation and function scores are reduced in young mice. In human islets, a similar pattern is observed in type 1 (T1D), but not type 2 (T2D), diabetes, suggesting that the impact of chronic IF in adolescence is linked to the development of β cell dysfunction. Our study suggests considering the duration of IF in younger persons, as it may worsen rather than reduce diabetes outcomes. AU - Matta Pereira, L. AU - Weber, P. AU - Erener, S. AU - Walth-Hummel, A.A. AU - Hass, D, AU - Bühler, L. AU - Klepac, K. AU - Szendroedi, J. AU - Garcia Guerra, J.F. AU - Rohm, M. AU - Sterr, M. AU - Lickert, H. AU - Bartelt, A. AU - Herzig, S. C1 - 73131 C2 - 56922 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Chronic intermittent fasting impairs β cell maturation and function in adolescent mice. JO - Cell Rep. VL - 44 IS - 2 PB - Cell Press PY - 2025 SN - 2211-1247 ER - TY - JOUR AB - Herein, we show a molecular pathway driven by an evolutionarily conserved microRNA (miRNA) in sensory neurons to control neuropathic pain. By employing high-throughput sequencing analysis, we find that miRNA-323-3p (miR-323-3p) exhibits the most significant upregulation in injured trigeminal ganglia (TGs). Local inhibition of miR-323-3p in injured TGs suppresses established trigeminal neuropathic pain but has no effect on inflammatory pain. Mechanistically, nerve injury upregulates the protein expression of protein arginine methyltransferase 2 (PRMT2), which promotes asymmetric dimethylation of H3R8, thereby facilitating the binding of the transcription factor forkhead box A2 (FOXA2) to the miR-323-3p promoter and resulting in the upregulation of miR-323-3p expression. Furthermore, the increased miR-323-3p expression induces significant reductions in Kv2.1 protein expression and channel currents, resulting in TG neuronal hyperexcitability. Conversely, the downregulation of miR-323-3p in injured TGs restores the decreased Kv2.1 expression and attenuates nerve-injury-induced mechanical hypersensitivity. The PRMT2/FOXA2/miR-323-3p/Kv2.1 signaling axis in sensory neurons may offer therapeutic targets in neuropathic pain management. AU - Qi, R.* AU - Tao, Y.* AU - Wang, S.* AU - Zhou, Y.* AU - Sun, Y.* AU - Jiang, D. AU - Huang, Z.* AU - Chen, G.* AU - Zhao, G.* AU - Zhang, Y.* AU - Rui, Y.* AU - Tao, J.* C1 - 75158 C2 - 57813 TI - PRMT2-mediated upregulation of miR-323-3p in sensory neurons promotes trigeminal neuropathic pain by targeting Kv2.1 channels. JO - Cell Rep. VL - 44 IS - 8 PY - 2025 SN - 2211-1247 ER - TY - JOUR AB - The role of neuropeptides and their receptors in oligodendrocyte (OL) progenitor cells (OPCs) has been largely overlooked so far. Here, we describe a new subpopulation of corticotropin-releasing hormone (CRH)-expressing OPCs. Brain injury rapidly induces transient CRH expression in OPCs that aggregate around injury sites and exhibit an elevated capacity to differentiate into myelinating OLs. As target cells, we identified CRH receptor type 1 (CRHR1)-expressing OPCs, which show a decreased differentiation velocity. CRH/CRHR1 system inactivation increases the speed of OL generation but compromises their long-term survival after acute injury. Under non-injury conditions, CRH/CRHR1 system deficiency leads to increased early postnatal oligodendrogenesis and alterations in adult myelination. Altogether, we show that OPC-derived CRH not only actively influences the injury environment through interaction with CRHR1-expressing OPCs but also identify the G-protein coupled receptor CRHR1 as a critical modulator of oligodendrogenesis during early postnatal development with lasting effects on adult myelination. AU - Ries, C.* AU - Stark, T.* AU - Boulat, B.* AU - Ruhwedel, T.* AU - Delling, J.P.* AU - Infante, A.M.* AU - von Poblotzki, J.T.* AU - Ulivi, A.F.* AU - von Mücke-Heim, I.A.* AU - Chang, S.C.-E. AU - Sakimura, K.* AU - Itoi, K.* AU - Nestvogel, D.B.* AU - Attardo, A.* AU - Czisch, M.* AU - Nave, K.A.* AU - Möbius, W.* AU - Dimou, L.* AU - Deussing, J.M.* C1 - 75920 C2 - 58196 TI - Neuropeptide CRH prevents premature differentiation of OPCs following CNS injury and in early postnatal development. JO - Cell Rep. VL - 44 IS - 11 PY - 2025 SN - 2211-1247 ER - TY - JOUR AB - Short-term transition to high-fat diet (HFD) feeding causes rapid changes in the molecular architecture of the blood-brain barrier (BBB), BBB permeability, and brain glucose uptake. However, the precise mechanisms responsible for these changes remain elusive. Here, we detect a rapid downregulation of Notch signaling after short-term HFD feeding. Conversely, Notch activation restores HFD-fed mouse serum-induced reduction of Glut1 expression and glycolysis in cultured brain microvascular endothelial cells (BMECs). Selective, inducible expression of the Notch intracellular domain (IC) in BMECs prevents HFD-induced reduction of Glut1 expression and hypothalamic glucose uptake. Caveolin (Cav)-1 expression in BMECs is increased upon short-term HFD feeding. However, NotchICBMECs mice display reduced caveola formation and BBB permeability. This ultimately translates into reduced hypothalamic insulin transport, action, and systemic insulin sensitivity. Collectively, we highlight a critical role of Notch signaling in the pleiotropic effects of short-term dietary transitions on BBB functionality. AU - Zhu, Y.* AU - Mehlkop, O.* AU - Backes, H.* AU - Cremer, A.L.* AU - Porniece, M.* AU - Klemm, P.* AU - Steuernagel, L.* AU - Chen, W.* AU - Johnen, R.* AU - Wunderlich, F.T.* AU - Jais, A. AU - Brüning, J.C.* C1 - 74469 C2 - 57486 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Reduced notch signaling in hypothalamic endothelial cells mediates obesity-induced alterations in glucose uptake and insulin signaling. JO - Cell Rep. VL - 44 IS - 4 PB - Cell Press PY - 2025 SN - 2211-1247 ER - TY - JOUR AB - Histopathological heterogeneity in the human pancreas is well documented; however, functional evidence at the tissue level is scarce. Herein, we investigate in situ glucose-stimulated islet and carbachol-stimulated acinar cell secretion across the pancreas head (PH), body (PB), and tail (PT) regions in donors without diabetes (ND; n = 15), positive for one islet autoantibody (1AAb+; n = 7), and with type 1 diabetes (T1D; <14 months duration, n = 5). Insulin, glucagon, pancreatic amylase, lipase, and trypsinogen secretion along with 3D tissue morphometrical features are comparable across regions in ND. In T1D, insulin secretion and beta-cell volume are significantly reduced within all regions, while glucagon and enzymes are unaltered. Beta-cell volume is lower despite normal insulin secretion in 1AAb+, resulting in increased volume-adjusted insulin secretion versus ND. Islet and acinar cell secretion in 1AAb+ are consistent across the PH, PB, and PT. This study supports low inter-regional variation in pancreas slice function and, potentially, increased metabolic demand in 1AAb+. AU - Drotar, D.M.* AU - Mojica Avila, A.K. AU - Bloss, D.T.* AU - Cohrs, C.M. AU - Manson, C.T.* AU - Posgai, A.L.* AU - Williams, M.D.* AU - Brusko, M.A.* AU - Phelps, E.A.* AU - Wasserfall, C.H.* AU - Speier, S. AU - Atkinson, M.A.* C1 - 70815 C2 - 55941 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Impaired islet function and normal exocrine enzyme secretion occur with low inter-regional variation in type 1 diabetes. JO - Cell Rep. VL - 43 IS - 6 PB - Cell Press PY - 2024 SN - 2211-1247 ER - TY - JOUR AB - Cardiometabolic diseases are leading causes of mortality in Western countries. Well-established risk factors include host genetics, lifestyle, diet, and the gut microbiome. Moreover, gut bacterial communities and their activities can be altered by bacteriophages (also known simply as phages), bacteria-infecting viruses, making these biological entities key regulators of human cardiometabolic health. The manipulation of bacterial populations by phages enables the possibility of using phages in the treatment of cardiometabolic diseases through phage therapy and fecal viral transplants. First, however, a deeper understanding of the role of the phageome in cardiometabolic diseases is required. In this review, we first introduce the phageome as a component of the gut microbiome and discuss fecal viral transplants and phage therapy in relation to cardiometabolic diseases. We then summarize the current state of phageome research in cardiometabolic diseases and propose how the phageome might indirectly influence cardiometabolic health through gut bacteria and their metabolites. AU - Kirk, D.* AU - Costeira, R.* AU - Visconti, A.* AU - Khan Mirzaei, M. AU - Deng, L. AU - Valdes, A.M.* AU - Menni, C.* C1 - 69894 C2 - 55311 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Bacteriophages, gut bacteria, and microbial pathways interplay in cardiometabolic health. JO - Cell Rep. VL - 43 IS - 2 PB - Cell Press PY - 2024 SN - 2211-1247 ER - TY - JOUR AB - Bak is a pore-forming Bcl2 protein that induces apoptosis at the outer mitochondrial membrane, which can either proceed via Bak oligomerization or be inhibited by anti-apoptotic Bcl2 proteins, such as BclxL. BclxL is very efficient in inhibiting Bak pore formation, but the mechanistic basis of this preferred interaction has remained enigmatic. Here, we identify Bakα1 as a second binding site for BclxL and show that it specifically interacts with the Bcl2-homology (BH)3 binding groove of BclxL. The affinity between BclxL and Bakα1 is weaker than with Bak-BH3, suggesting that Bakα1, being exposed early in the pore-forming trajectory, transiently captures BclxL, which subsequently transitions to the proximal BH3 site. Bak variants where the initial transient interaction with BclxL is modulated show a markedly altered response to BclxL inhibition. This work contributes to a better mechanistic understanding of the fine-tuned interactions between different players of the Bcl2 protein family. AU - Leitl, K. AU - Sperl, L.E.* AU - Hagn, F. C1 - 71302 C2 - 56038 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Preferred inhibition of pro-apoptotic Bak by BclxL via a two-step mechanism. JO - Cell Rep. VL - 43 IS - 8 PB - Cell Press PY - 2024 SN - 2211-1247 ER - TY - JOUR AB - The metabolic syndrome is accompanied by vascular complications. Human in vitro disease models are hence required to better understand vascular dysfunctions and guide clinical therapies. Here, we engineered an open microfluidic vessel-on-chip platform that integrates human pluripotent stem cell-derived endothelial cells (SC-ECs). The open microfluidic design enables seamless integration with state-of-the-art analytical technologies, including single-cell RNA sequencing, proteomics by mass spectrometry, and high-resolution imaging. Beyond previous systems, we report SC-EC maturation by means of barrier formation, arterial toning, and high nitric oxide synthesis levels under gravity-driven flow. Functionally, we corroborate the hallmarks of early-onset atherosclerosis with low sample volumes and cell numbers under flow conditions by determining proteome and secretome changes in SC-ECs stimulated with oxidized low-density lipoprotein and free fatty acids. More broadly, our organ-on-chip platform enables the modeling of patient-specific human endothelial tissue and has the potential to become a general tool for animal-free vascular research. AU - Marder, M. AU - Remmert, C. AU - Perschel, J.A. AU - Otgonbayar, M. AU - von Toerne, C. AU - Hauck, S.M. AU - Bushe, J. AU - Feuchtinger, A. AU - Sheikh, B. AU - Moussus, M. AU - Meier, M. C1 - 70387 C2 - 55553 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Stem cell-derived vessels-on-chip for cardiovascular disease modeling. JO - Cell Rep. VL - 43 IS - 4 PB - Cell Press PY - 2024 SN - 2211-1247 ER - TY - JOUR AB - Endocrine cells employ regulated exocytosis of secretory granules to secrete hormones and neurotransmitters. Secretory granule exocytosis depends on spatiotemporal variables such as proximity to the plasma membrane and age, with newly generated granules being preferentially released. Despite recent advances, we lack a comprehensive view of the molecular composition of insulin granules and associated changes over their lifetime. Here, we report a strategy for the purification of insulin secretory granules of distinct age from insulinoma INS-1 cells. Tagging the granule-resident protein phogrin with a cleavable CLIP tag, we obtain intact fractions of age-distinct granules for proteomic and lipidomic analyses. We find that the lipid composition changes over time, along with the physical properties of the membrane, and that kinesin-1 heavy chain (KIF5b) as well as Ras-related protein 3a (RAB3a) associate preferentially with younger granules. Further, we identify the Rho GTPase-activating protein (ARHGAP1) as a cytosolic factor associated with insulin granules. AU - Neukam, M. AU - Sala, P. AU - Brunner, A.D.* AU - Ganß, K. AU - Palladini, A. AU - Grzybek, M. AU - Topcheva, O. AU - Vasiljevic, J. AU - Broichhagen, J.* AU - Johnsson, K.* AU - Kurth, T.* AU - Mann, M.* AU - Coskun, Ü. AU - Solimena, M. C1 - 70103 C2 - 55423 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Purification of time-resolved insulin granules reveals proteomic and lipidomic changes during granule aging. JO - Cell Rep. VL - 43 IS - 3 PB - Cell Press PY - 2024 SN - 2211-1247 ER - TY - JOUR AB - Insulin is packaged into secretory granules that depart the Golgi and undergo a maturation process that involves changes in the protein and lipid composition of the granules. Here, we show that insulin secretory granules form physical contacts with the endoplasmic reticulum and that the lipid exchange protein oxysterol-binding protein (OSBP) is recruited to these sites in a Ca2+-dependent manner. OSBP binding to insulin granules is positively regulated by phosphatidylinositol-4 (PI4)-kinases and negatively regulated by the PI4 phosphate (PI(4)P) phosphatase Sac2. Loss of Sac2 results in excess accumulation of cholesterol on insulin granules that is normalized when OSBP expression is reduced, and both acute inhibition and small interfering RNA (siRNA)-mediated knockdown of OSBP suppress glucose-stimulated insulin secretion without affecting insulin production or intracellular Ca2+ signaling. In conclusion, we show that lipid exchange at endoplasmic reticulum (ER)-granule contact sites is involved in the exocytic process and propose that these contacts act as reaction centers with multimodal functions during insulin granule maturation. AU - Panagiotou, S.* AU - Tan, K.W.* AU - Nguyen, P.M.* AU - Müller, A. AU - Oqua, A.I.* AU - Tomas, A.* AU - Wendt, A.* AU - Eliasson, L.* AU - Tengholm, A.* AU - Solimena, M. AU - Idevall-Hagren, O.* C1 - 70388 C2 - 55554 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - OSBP-mediated PI(4)P-cholesterol exchange at endoplasmic reticulum-secretory granule contact sites controls insulin secretion. JO - Cell Rep. VL - 43 IS - 4 PB - Cell Press PY - 2024 SN - 2211-1247 ER - TY - JOUR AB - The significance of thyroid hormones (THs) in beige adipocyte thermogenesis remains incompletely understood. We previously reported that THs directly regulate the expression of zinc-finger protein 423 (ZFP423), an anti-thermogenic factor, in adipose tissue. This study investigates the interaction between THs and adrenergic signaling in regulating thermogenic capacity and activation of beige adipocytes formed in response to Zfp423 deletion. We demonstrate that THs are indispensable for uncoupling protein 1 (UCP1)-dependent thermogenesis, leading to increased energy expenditure in mice with adipocyte-specific Zfp423 knockout. Targeted activation of the thyroid receptor isoform TRβ, which plays a central role in the inguinal depot, is sufficient to enhance energy expenditure in hypothyroid Zfp423iAKO mice. Mechanistically, THs and ZFP423 pathways cooperate to regulate early B cell factor 2 (EBF2)-mediated activation of the Ucp1 gene. RNA sequencing (RNA-seq) analysis of human adipose tissue samples supports the relevance of this regulatory network for human adipose tissue plasticity. AU - Roth, L.* AU - Hoffmann, A. AU - Hagemann, T. AU - Wagner, L.* AU - Strehlau, C. AU - Sheikh, B. AU - Donndorf, L. AU - Ghosh, A.* AU - Noé, F.* AU - Wolfrum, C.* AU - Krohn, K.* AU - Weiner, J.* AU - Heiker, J.T. AU - Klöting, N. AU - Stumvoll, M. AU - Tönjes, A.* AU - Blüher, M. AU - Mittag, J.* AU - Krause, K.* C1 - 72522 C2 - 56639 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Thyroid hormones are required for thermogenesis of beige adipocytes induced by Zfp423 inactivation. JO - Cell Rep. VL - 43 IS - 12 PB - Cell Press PY - 2024 SN - 2211-1247 ER - TY - JOUR AB - Activation of prepronociceptin (PNOC)-expressing neurons in the arcuate nucleus (ARC) promotes high-fat-diet (HFD)-induced hyperphagia. In turn, PNOCARC neurons can inhibit the anorexic response of proopiomelanocortin (POMC) neurons. Here, we validate the necessity of PNOCARC activity for HFD-induced inhibition of POMC neurons in mice and find that PNOCARC-neuron-dependent inhibition of POMC neurons is mediated by gamma-aminobutyric acid (GABA) release. When monitoring individual PNOCARC neuron activity via Ca2+ imaging, we find a subpopulation of PNOCARC neurons that is inhibited upon gastrointestinal calorie sensing and disinhibited upon HFD feeding. Combining retrograde rabies tracing and circuit mapping, we find that PNOC neurons from the bed nucleus of the stria terminalis (PNOCBNST) provide inhibitory input to PNOCARC neurons, and this inhibitory input is blunted upon HFD feeding. This work sheds light on how an increase in caloric content of the diet can rewire a neuronal circuit, paving the way to overconsumption and obesity development. AU - Sotelo-Hitschfeld, T.* AU - Minère, M.* AU - Klemm, P.* AU - Borgmann, D.* AU - Wnuk-Lipinski, D.* AU - Jais, A. AU - Jia, X.* AU - Corneliussen, S.* AU - Kloppenburg, P.* AU - Fenselau, H.* AU - Brüning, J.C.* C1 - 70825 C2 - 55944 TI - GABAergic disinhibition from the BNST to PNOCARC neurons promotes HFD-induced hyperphagia. JO - Cell Rep. VL - 43 IS - 6 PY - 2024 SN - 2211-1247 ER - TY - JOUR AB - Metabolism oscillates between catabolic and anabolic states depending on food intake, exercise, or stresses that change a multitude of metabolic pathways simultaneously. We present the HuMet Repository for exploring dynamic metabolic responses to oral glucose/lipid loads, mixed meals, 36-h fasting, exercise, and cold stress in healthy subjects. Metabolomics data from blood, urine, and breath of 15 young, healthy men at up to 56 time points are integrated and embedded within an interactive web application, enabling researchers with and without computational expertise to search, visualize, analyze, and contextualize the dynamic metabolite profiles of 2,656 metabolites acquired on multiple platforms. With examples, we demonstrate the utility of the resource for research into the dynamics of human metabolism, highlighting differences and similarities in systemic metabolic responses across challenges and the complementarity of metabolomics platforms. The repository, providing a reference for healthy metabolite changes to six standardized physiological challenges, is freely accessible through a web portal. AU - Weinisch, P. AU - Raffler, J. AU - Römisch-Margl, W. AU - Arnold, M. AU - Mohney, R.P.* AU - Rist, M.J.* AU - Prehn, C. AU - Skurk, T.* AU - Hauner, H.* AU - Daniel, H.* AU - Suhre, K.* AU - Kastenmüller, G. C1 - 71246 C2 - 55960 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - The HuMet Repository: Watching human metabolism at work. JO - Cell Rep. VL - 43 IS - 8 PB - Cell Press PY - 2024 SN - 2211-1247 ER - TY - JOUR AB - Recent advances in synthetic embryology have opened new avenues for understanding the complex events controlling mammalian peri-implantation development. Here, we show that mouse embryonic stem cells (ESCs) solely exposed to chemical inhibition of SUMOylation generate embryo-like structures comprising anterior neural and trunk-associated regions. HypoSUMOylation-instructed ESCs give rise to spheroids that self-organize into gastrulating structures containing cell types spatially and functionally related to embryonic and extraembryonic compartments. Alternatively, spheroids cultured in a droplet microfluidic device form elongated structures that undergo axial organization reminiscent of natural embryo morphogenesis. Single-cell transcriptomics reveals various cellular lineages, including properly positioned anterior neuronal cell types and paraxial mesoderm segmented into somite-like structures. Transient SUMOylation suppression gradually increases DNA methylation genome wide and repressive mark deposition at Nanog. Interestingly, cell-to-cell variations in SUMOylation levels occur during early embryogenesis. Our approach provides a proof of principle for potentially powerful strategies to explore early embryogenesis by targeting chromatin roadblocks of cell fate change. AU - Cossec, J.C.* AU - Traboulsi, T.* AU - Sart, S.* AU - Loe-Mie, Y.* AU - Guthmann, M. AU - Hendriks, I.A.* AU - Theurillat, I.* AU - Nielsen, M.L.* AU - Torres-Padilla, M.E. AU - Baroud, C.N.* AU - Dejean, A.* C1 - 67604 C2 - 53911 TI - Transient suppression of SUMOylation in embryonic stem cells generates embryo-like structures. JO - Cell Rep. VL - 42 IS - 4 PY - 2023 SN - 2211-1247 ER - TY - JOUR AB - Metabolic rewiring is essential for cancer onset and progression. We previously showed that one-carbon metabolism-dependent formate production often exceeds the anabolic demand of cancer cells, resulting in formate overflow. Furthermore, we showed that increased extracellular formate concentrations promote the in vitro invasiveness of glioblastoma cells. Here, we substantiate these initial observations with ex vivo and in vivo experiments. We also show that exposure to exogeneous formate can prime cancer cells toward a pro-invasive phenotype leading to increased metastasis formation in vivo. Our results suggest that the increased local formate concentration within the tumor microenvironment can be one factor to promote metastases. Additionally, we describe a mechanistic interplay between formate-dependent increased invasiveness and adaptations of lipid metabolism and matrix metalloproteinase activity. Our findings consolidate the role of formate as pro-invasive metabolite and warrant further research to better understand the interplay between formate and lipid metabolism. AU - Delbrouck, C.* AU - Kiweler, N.* AU - Chen, O.* AU - Pozdeev, V.I.* AU - Haase, L.* AU - Neises, L.* AU - Oudin, A.* AU - Fouquier d'Hérouël, A.* AU - Shen, R. AU - Schlicker, L.* AU - Halder, R.* AU - Lesur, A.* AU - Schuster, A.* AU - Lorenz, N.I.* AU - Jaeger, C.* AU - Feucherolles, M.* AU - Frache, G.* AU - Szpakowska, M.* AU - Chevigne, A.* AU - Ronellenfitsch, M.W.* AU - Moussay, E.* AU - Piraud, M. AU - Skupin, A.* AU - Schulze, A.* AU - Niclou, S.P.* AU - Letellier, E.* AU - Meiser, J.* C1 - 68320 C2 - 54759 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Formate promotes invasion and metastasis in reliance on lipid metabolism. JO - Cell Rep. VL - 42 IS - 9 PB - Cell Press PY - 2023 SN - 2211-1247 ER - TY - JOUR AB - Human pre-mRNA splicing requires the removal of introns with highly variable lengths, from tens to over a million nucleotides. Therefore, mechanisms of intron recognition and splicing are likely not universal. Recently, we reported that splicing in a subset of human short introns with truncated polypyrimidine tracts depends on RBM17 (SPF45), instead of the canonical splicing factor U2 auxiliary factor (U2AF) heterodimer. Here, we demonstrate that SAP30BP, a factor previously implicated in transcriptional control, is an essential splicing cofactor for RBM17. In vitro binding and nuclear magnetic resonance analyses demonstrate that a U2AF-homology motif (UHM) in RBM17 binds directly to a newly identified UHM-ligand motif in SAP30BP. We show that this RBM17-SAP30BP interaction is required to specifically recruit RBM17 to phosphorylated SF3B1 (SF3b155), a U2 small nuclear ribonucleoprotein (U2 snRNP) component in active spliceosomes. We propose a mechanism for splicing in a subset of short introns, in which SAP30BP guides RBM17 in the assembly of active spliceosomes. AU - Fukumura, K.* AU - Sperotto, L. AU - Seuss, S. AU - Kang, H.-S. AU - Yoshimoto, R.* AU - Sattler, M. AU - Mayeda, A.* C1 - 68933 C2 - 53775 TI - SAP30BP interacts with RBM17/SPF45 to promote splicing in a subset of human short introns. JO - Cell Rep. PY - 2023 SN - 2211-1247 ER - TY - JOUR AB - Oxytocin-expressing paraventricular hypothalamic neurons (PVNOT neurons) integrate afferent signals from the gut, including cholecystokinin (CCK), to adjust whole-body energy homeostasis. However, the molecular underpinnings by which PVNOT neurons orchestrate gut-to-brain feeding control remain unclear. Here, we show that mice undergoing selective ablation of PVNOT neurons fail to reduce food intake in response to CCK and develop hyperphagic obesity on a chow diet. Notably, exposing wild-type mice to a high-fat/high-sugar (HFHS) diet recapitulates this insensitivity toward CCK, which is linked to diet-induced transcriptional and electrophysiological aberrations specifically in PVNOT neurons. Restoring OT pathways in diet-induced obese (DIO) mice via chemogenetics or polypharmacology sufficiently re-establishes CCK's anorexigenic effects. Last, by single-cell profiling, we identify a specialized PVNOT neuronal subpopulation with increased κ-opioid signaling under an HFHS diet, which restrains their CCK-evoked activation. In sum, we document a (patho)mechanism by which PVNOT signaling uncouples a gut-brain satiation pathway under obesogenic conditions. AU - Gruber, T. AU - Contreras, R. AU - Sánchez Quant, E.S. AU - Miok, V. AU - Makris, K. AU - Le Thuc, O. AU - Gonzales García, I. AU - Garcia-Clavé, E. AU - Althammer, F.* AU - Krabichler, Q.* AU - DeCamp, L.M.* AU - Jones, R.G.* AU - Lutter, D. AU - Williams, R.H. AU - Pfluger, P.T. AU - Müller, T.D. AU - Woods, S.C.* AU - Pospisilik, J.A.* AU - Martinez-Jimenez, C.P.* AU - Tschöp, M.H. AU - Grinevich, V.* AU - García-Cáceres, C. C1 - 68711 C2 - 54920 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - High-calorie diets uncouple hypothalamic oxytocin neurons from a gut-to-brain satiation pathway via κ-opioid signaling. JO - Cell Rep. VL - 42 IS - 10 PB - Cell Press PY - 2023 SN - 2211-1247 ER - TY - JOUR AB - Fibrosis represents the common end stage of chronic organ injury independent of the initial insult, destroying tissue architecture and driving organ failure. Here we discover a population of profibrotic macrophages marked by expression of Spp1, Fn1, and Arg1 (termed Spp1 macrophages), which expands after organ injury. Using an unbiased approach, we identify the chemokine (C-X-C motif) ligand 4 (CXCL4) to be among the top upregulated genes during profibrotic Spp1 macrophage differentiation. In vitro and in vivo studies show that loss of Cxcl4 abrogates profibrotic Spp1 macrophage differentiation and ameliorates fibrosis after both heart and kidney injury. Moreover, we find that platelets, the most abundant source of CXCL4 in vivo, drive profibrotic Spp1 macrophage differentiation. Single nuclear RNA sequencing with ligand-receptor interaction analysis reveals that macrophages orchestrate fibroblast activation via Spp1, Fn1, and Sema3 crosstalk. Finally, we confirm that Spp1 macrophages expand in both human chronic kidney disease and heart failure. AU - Hoeft, K.* AU - Schaefer, G.J.L.* AU - Kim, H.* AU - Schumacher, D.* AU - Bleckwehl, T.* AU - Long, Q.* AU - Klinkhammer, B.M.* AU - Peisker, F.* AU - Koch, L.* AU - Nagai, J.* AU - Halder, M.* AU - Ziegler, S.* AU - Liehn, E.* AU - Kuppe, C.* AU - Kranz, J.* AU - Menzel, S.* AU - Costa, I.* AU - Wahida, A. AU - Boor, P.* AU - Schneider, R.K.* AU - Hayat, S.* AU - Kramann, R.* C1 - 67454 C2 - 54111 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Platelet-instructed SPP1+ macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner. JO - Cell Rep. VL - 42 IS - 2 PB - Cell Press PY - 2023 SN - 2211-1247 ER - TY - JOUR AB - Systemic inflammation is established as part of late-stage severe lung disease, but molecular, functional, and phenotypic changes in peripheral immune cells in early disease stages remain ill defined. Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small-airway inflammation, emphysema, and severe breathing difficulties. Using single-cell analyses we demonstrate that blood neutrophils are already increased in early-stage COPD, and changes in molecular and functional neutrophil states correlate with lung function decline. Assessing neutrophils and their bone marrow precursors in a murine cigarette smoke exposure model identified similar molecular changes in blood neutrophils and precursor populations that also occur in the blood and lung. Our study shows that systemic molecular alterations in neutrophils and their precursors are part of early-stage COPD, a finding to be further explored for potential therapeutic targets and biomarkers for early diagnosis and patient stratification. AU - Kapellos, T. AU - Baßler, K.* AU - Fujii, W.* AU - Nalkurthi, C.* AU - Schaar, A. AU - Bonaguro, L.* AU - Pecht, T.* AU - Galvao, I.* AU - Agrawal, S.* AU - Saglam, A.* AU - Dudkin, E.* AU - Frishberg, A. AU - De Domenico, E.* AU - Horne, A.* AU - Donovan, C.* AU - Kim, R.Y.* AU - Gallego-Ortega, D.* AU - Gillett, T.E.* AU - Ansari, M. AU - Schulte-Schrepping, J.* AU - Offermann, N.* AU - Antignano, I.* AU - Sivri, B.* AU - Lu, W.* AU - Eapen, M.S.* AU - van Uelft, M.* AU - Osei-Sarpong, C.* AU - van den Berge, M.* AU - Donker, H.C.* AU - Groen, H.J.M.* AU - Sohal, S.S.* AU - Klein, J.* AU - Schreiber, T.* AU - Feißt, A.* AU - Yildirim, A.Ö. AU - Schiller, H. AU - Nawijn, M.C.* AU - Becker, M.* AU - Händler, K.* AU - Beyer, M.* AU - Capasso, M.* AU - Ulas, T.* AU - Hasenauer, J. AU - Pizarro, C.* AU - Theis, F.J. AU - Hansbro, P.M.* AU - Skowasch, D.* AU - Schultze, J. C1 - 67875 C2 - 54353 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Systemic alterations in neutrophils and their precursors in early-stage chronic obstructive pulmonary disease. JO - Cell Rep. VL - 42 IS - 6 PB - Cell Press PY - 2023 SN - 2211-1247 ER - TY - JOUR AB - SORL1 is implicated in the pathogenesis of Alzheimer's disease (AD) through genetic studies. To interrogate the roles of SORL1 in human brain cells, SORL1-null induced pluripotent stem cells (iPSCs) were differentiated to neuron, astrocyte, microglial, and endothelial cell fates. Loss of SORL1 leads to alterations in both overlapping and distinct pathways across cell types, with the greatest effects in neurons and astrocytes. SORL1 loss induces a neuron-specific reduction in apolipoprotein E (APOE) and clusterin (CLU) and altered lipid profiles. Analyses of iPSCs derived from a large cohort reveal a neuron-specific association between SORL1, APOE, and CLU levels, a finding validated in postmortem brain. Enhancement of retromer-mediated trafficking rescues tau phenotypes observed in SORL1-null neurons but does not rescue APOE levels. Pathway analyses implicate transforming growth factor β (TGF-β)/SMAD signaling in SORL1 function, and modulating SMAD signaling in neurons alters APOE RNA levels in a SORL1-dependent manner. Taken together, these data provide a mechanistic link between strong genetic risk factors for AD. AU - Lee, H.* AU - Aylward, A.J.* AU - Pearse, R.V.* AU - Lish, A.M.* AU - Hsieh, Y.C.* AU - Augur, Z.M.* AU - Benoit, C.R.* AU - Chou, V.* AU - Knupp, A.* AU - Pan, C.* AU - Goberdhan, S.* AU - Duong, D.M.* AU - Seyfried, N.T.* AU - Bennett, D.A.* AU - Taga, M.F.* AU - Huynh, K.* AU - Arnold, M. AU - Meikle, P.J.* AU - de Jager, P.L.* AU - Menon, V.* AU - Young, J.E.* AU - Young-Pearse, T.L.* C1 - 67966 C2 - 54444 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer's disease risk gene SORL1. JO - Cell Rep. VL - 42 IS - 8 PB - Cell Press PY - 2023 SN - 2211-1247 ER - TY - JOUR AB - The hypothalamic pituitary thyroid axis is a major regulator of many differentiation processes, including adipose tissue. However, it remains unclear whether and how thyroid hormone (TH) signaling contributes to preadipocyte commitment and differentiation into mature adipocytes. Here, we show a cell-autonomous effect of TH on the transcriptional regulation of zinc finger protein 423 (Zfp423), an early adipogenic determination factor, in murine adipose depots. Mechanistically, binding of the unliganded TH receptor to a negative TH responsive element within the Zfp423 promoter activates transcriptional activity that is reversed upon TH binding. Zfp423 upregulation is associated with increased GFP+ preadipocyte recruitment in stromal vascular fraction isolated from white fat of hypothyroid Zfp423GFP reporter mice. RNA sequencing identified Zfp423-driven gene programs that are modulated in response to TH during adipogenic differentiation. Collectively, we identified Zfp423 as a key molecule that integrates TH signaling into the regulation of adipose tissue plasticity. AU - Roth, L.* AU - Johann, K.* AU - Hönes, G.S.* AU - Oelkrug, R.* AU - Wagner, L.* AU - Hoffmann, A. AU - Krohn, K.* AU - Moeller, L.C.* AU - Weiner, J.* AU - Heiker, J.T. AU - Klöting, N. AU - Tönjes, A.* AU - Stumvoll, M. AU - Blüher, M. AU - Mittag, J.* AU - Krause, K.* C1 - 67426 C2 - 54150 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Thyroid hormones regulate Zfp423 expression in regionally distinct adipose depots through direct and cell-autonomous action. JO - Cell Rep. VL - 42 IS - 2 PB - Cell Press PY - 2023 SN - 2211-1247 ER - TY - JOUR AB - The acquisition of mesenchymal traits is considered a hallmark of breast cancer progression. However, the functional relevance of epithelial-to-mesenchymal transition (EMT) remains controversial and context dependent. Here, we isolate epithelial and mesenchymal populations from human breast cancer metastatic biopsies and assess their functional potential in vivo. Strikingly, progressively decreasing epithelial cell adhesion molecule (EPCAM) levels correlate with declining disease propagation. Mechanistically, we find that persistent EPCAM expression marks epithelial clones that resist EMT induction and propagate competitively. In contrast, loss of EPCAM defines clones arrested in a mesenchymal state, with concomitant suppression of tumorigenicity and metastatic potential. This dichotomy results from distinct clonal trajectories impacting global epigenetic programs that are determined by the interplay between human ZEB1 and its target GRHL2. Collectively, our results indicate that susceptibility to irreversible EMT restrains clonal propagation, whereas resistance to mesenchymal reprogramming sustains disease spread in multiple models of human metastatic breast cancer, including patient-derived cells in vivo. AU - Saini, M. AU - Schmidleitner, L. AU - Moreno, H.D.* AU - Donato, E.* AU - Falcone, M.* AU - Bartsch, J. AU - Klein, C.* AU - Vogel, V.* AU - Würth, R.* AU - Pfarr, N.* AU - Espinet, E.* AU - Lehmann, M. AU - Königshoff, M. AU - Reitberger, M.* AU - Haas, S.* AU - Graf, E. AU - Schwarzmayr, T. AU - Strom, T.M. AU - Spaich, S.* AU - Sütterlin, M.* AU - Schneeweiss, A.* AU - Weichert, W.* AU - Schotta, G.* AU - Reichert, M.* AU - Aceto, N.* AU - Sprick, M.R.* AU - Trumpp, A.* AU - Scheel, C. C1 - 67865 C2 - 54343 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Resistance to mesenchymal reprogramming sustains clonal propagation in metastatic breast cancer. JO - Cell Rep. VL - 42 IS - 6 PB - Cell Press PY - 2023 SN - 2211-1247 ER - TY - JOUR AB - The chromatin environment at origins of replication is thought to influence DNA replication initiation in eukaryotic genomes. However, it remains unclear how and which chromatin features control the firing of early-efficient (EE) or late-inefficient (LI) origins. Here, we use site-specific recombination and single-locus chromatin isolation to purify EE and LI replication origins in Saccharomyces cerevisiae. Using mass spectrometry, we define the protein composition of native chromatin regions surrounding the EE and LI replication start sites. In addition to known origin interactors, we find the microtubule-binding Ask1/DASH complex as an origin-regulating factor. Strikingly, tethering of Ask1 to individual origin sites advances replication timing (RT) of the targeted chromosomal domain. Targeted degradation of Ask1 globally changes RT of a subset of origins, which can be reproduced by inhibiting microtubule dynamics. Thus, our findings mechanistically connect RT and chromosomal organization via Ask1/DASH with the microtubule cytoskeleton. AU - Weiß, M. AU - Chanou, A. AU - Schauer, T. AU - Tvardovskiy, A. AU - Meiser, S. AU - König, A.-C. AU - Schmidt, T. AU - Kruse, E. AU - Ummethum, H. AU - Trauner, M. AU - Werner, M. AU - Lalonde, M. AU - Hauck, S.M. AU - Scialdone, A. AU - Hamperl, S. C1 - 67353 C2 - 54189 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Single-copy locus proteomics of early- and late-firing DNA replication origins identifies a role of Ask1/DASH complex in replication timing control. JO - Cell Rep. VL - 42 IS - 2 PB - Cell Press PY - 2023 SN - 2211-1247 ER - TY - JOUR AB - How transcription is regulated as development commences is fundamental to understand how the transcriptionally silent mature gametes are reprogrammed. The embryonic genome is activated for the first time during zygotic genome activation (ZGA). How RNA polymerase II (Pol II) and productive elongation are regulated during this process remains elusive. Here, we generate genome-wide maps of Serine 5 and Serine 2-phosphorylated Pol II during and after ZGA in mouse embryos. We find that both phosphorylated Pol II forms display similar distributions across genes during ZGA, with typical elongation enrichment of Pol II emerging after ZGA. Serine 2-phosphorylated Pol II occurs at genes prior to their activation, suggesting that Serine 2 phosphorylation may prime gene expression. Functional perturbations demonstrate that CDK9 and SPT5 are major ZGA regulators and that SPT5 prevents precocious activation of some genes. Overall, our work sheds molecular insights into transcriptional regulation at the beginning of mammalian development. AU - Abe, K. AU - Schauer, T. AU - Torres-Padilla, M.E. C1 - 67073 C2 - 53447 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Distinct patterns of RNA polymerase II and transcriptional elongation characterize mammalian genome activation. JO - Cell Rep. VL - 41 IS - 13 PB - Cell Press PY - 2022 SN - 2211-1247 ER - TY - JOUR AB - Therapies based on glucagon-like peptide-1 (GLP-1) long-acting analogs and insulin are often used in the treatment of metabolic diseases. Both insulin and GLP-1 receptors are expressed in metabolically relevant brain regions, suggesting a cooperative action. However, the mechanisms underlying the synergistic actions of insulin and GLP-1R agonists remain elusive. In this study, we show that insulin-induced hypoglycemia enhances GLP-1R agonists entry in hypothalamic and area, leading to enhanced whole-body fat oxidation. Mechanistically, this phenomenon relies on the release of tanycyctic vascular endothelial growth factor A, which is selectively impaired after calorie-rich diet exposure. In humans, low blood glucose also correlates with enhanced blood-to-brain passage of insulin, suggesting that blood glucose gates the passage other energy-related signals in the brain. This study implies that the preventing hyperglycemia is important to harnessing the full benefit of GLP-1R agonist entry in the brain and action onto lipid mobilization and body weight loss. AU - Bakker, W.* AU - Imbernon, M.* AU - Salinas, C.G.* AU - Moro Chao, D.H.* AU - Hassouna, R.* AU - Morel, C.* AU - Martin, C.* AU - Leger, C.* AU - Denis, R.G.P.* AU - Castel, J.* AU - Peter, A. AU - Heni, M. AU - Maetzler, W.* AU - Nielsen, H.S.* AU - Duquenne, M.* AU - Schwaninger, M.* AU - Lundh, S.* AU - Johan Hogendorf, W.F.* AU - Gangarossa, G.* AU - Secher, A.* AU - Hecksher-Sørensen, J.* AU - Pedersen, T.Å.* AU - Prévot, V.* AU - Luquet, S.* C1 - 66767 C2 - 53299 TI - Acute changes in systemic glycemia gate access and action of GLP-1R agonist on brain structures controlling energy homeostasis. JO - Cell Rep. VL - 41 IS - 8 PY - 2022 SN - 2211-1247 ER - TY - JOUR AB - Liver sinusoidal endothelial cells (LSECs) are liver-resident antigen (cross)-presenting cells that generate memory CD8 T cells, but metabolic properties of LSECs and LSEC-primed CD8 T cells remain understudied. Here, we report that high-level mitochondrial respiration and constitutive low-level glycolysis support LSEC scavenger and sentinel functions. LSECs fail to increase glycolysis and co-stimulation after TLR4 activation, indicating absence of metabolic and functional maturation compared with immunogenic dendritic cells. LSEC-primed CD8 T cells show a transient burst of oxidative phosphorylation and glycolysis. Mechanistically, co-stimulatory IL-6 signaling ensures high FOXO1 expression in LSEC-primed CD8 T cells, curtails metabolic activity associated with T cell activation, and is indispensable for T cell functionality after re-activation. Thus, distinct immunometabolic features characterize non-immunogenic LSECs compared with immunogenic dendritic cells and LSEC-primed CD8 T cells with memory features compared with effector CD8 T cells. This reveals local features of metabolism and function of T cells in the liver. AU - Dudek, M.* AU - Lohr, K.* AU - Donakonda, S.* AU - Baumann, T.* AU - Lüdemann, M.* AU - Hegenbarth, S.* AU - Dübbel, L.* AU - Eberhagen, C. AU - Michailidou, S.* AU - Yassin, A.* AU - Prinz, M.* AU - Popper, B.* AU - Rose-John, S.* AU - Zischka, H. AU - Knolle, P.A.* C1 - 64335 C2 - 51965 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - IL-6-induced FOXO1 activity determines the dynamics of metabolism in CD8 T cells cross-primed by liver sinusoidal endothelial cells. JO - Cell Rep. VL - 38 IS - 7 PB - Cell Press PY - 2022 SN - 2211-1247 ER - TY - JOUR AB - Gastric bypass and vertical sleeve gastrectomy (VSG) remain the most potent and durable treatments for obesity and type 2 diabetes but are also associated with iron deficiency. The transcription factor HIF2α, which regulates iron absorption in the duodenum, increases following these surgeries. Increasing iron levels by means of dietary supplementation or hepatic hepcidin knockdown does not undermine the effects of VSG, indicating that metabolic improvements following VSG are not secondary to lower iron levels. Gut-specific deletion of Vhl results in increased constitutive duodenal HIF2α signaling and produces a profound lean, glucose-tolerant phenotype that mimics key effects of VSG. Interestingly, intestinal Vhl deletion also results in increased intestinal secretion of GLP-1, which is essential for these metabolic benefits. These data demonstrate a role for increased duodenal HIF2α signaling in regulating crosstalk between iron-regulatory systems and other aspects of systemic physiology important for metabolic regulation. AU - Evers, S.S.* AU - Shao, Y.* AU - Ramakrishnan, S.K.* AU - Shin, J.H.* AU - Bozadjieva-Kramer, N.* AU - Irmler, M. AU - Stemmer, K. AU - Sandoval, D.A.* AU - Shah, Y.M.* AU - Seeley, R.J.* C1 - 64123 C2 - 51809 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Gut HIF2α signaling is increased after VSG, and gut activation of HIF2α decreases weight, improves glucose, and increases GLP-1 secretion. JO - Cell Rep. VL - 38 IS - 3 PB - Cell Press PY - 2022 SN - 2211-1247 ER - TY - JOUR AB - In hepatocytes, peroxisome proliferator-activated receptor α (PPARα) orchestrates a genomic and metabolic response required for homeostasis during fasting. This includes the biosynthesis of ketone bodies and of fibroblast growth factor 21 (FGF21). Here we show that in the absence of adipose triglyceride lipase (ATGL) in adipocytes, ketone body and FGF21 production is impaired upon fasting. Liver gene expression analysis highlights a set of fasting-induced genes sensitive to both ATGL deletion in adipocytes and PPARα deletion in hepatocytes. Adipose tissue lipolysis induced by activation of the β3-adrenergic receptor also triggers such PPARα-dependent responses not only in the liver but also in brown adipose tissue (BAT). Intact PPARα activity in hepatocytes is required for the cross-talk between adipose tissues and the liver during fat mobilization. AU - Fougerat, A.* AU - Schoiswohl, G.* AU - Polizzi, A.* AU - Régnier, M.* AU - Wagner, C.* AU - Smati, S.* AU - Fougeray, T.* AU - Lippi, Y.* AU - Lasserre, F.* AU - Raho, I.* AU - Melin, V.* AU - Tramunt, B.* AU - Métivier, R.* AU - Sommer, C.* AU - Benhamed, F.* AU - Alkhoury, C.* AU - Greulich, F.* AU - Jouffe, C. AU - Emile, A.* AU - Schupp, M.* AU - Gourdy, P.* AU - Dubot, P.* AU - Levade, T.* AU - Meynard, D.* AU - Ellero-Simatos, S.* AU - Gamet-Payrastre, L.* AU - Panasyuk, G.* AU - Uhlenhaut, N.H. AU - Amri, E.Z.* AU - Cruciani-Guglielmacci, C.* AU - Postic, C.* AU - Wahli, W.* AU - Loiseau, N.* AU - Montagner, A.* AU - Langin, D.* AU - Lass, A.* AU - Guillou, H.* C1 - 65453 C2 - 52306 TI - ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity. JO - Cell Rep. VL - 39 IS - 10 PY - 2022 SN - 2211-1247 ER - TY - JOUR AB - Asymmetric inheritance of cellular content through cell division plays an important role in cell viability and fitness. The dynamics of RNA segregation are so far largely unaddressed. This is partly due to a lack of approaches to follow RNAs over multiple cellular divisions. Here, we establish an approach to quantify RNA dynamics in single cells across several generations in a microfluidics device by tagging RNAs with the diSpinach aptamer. Using S. cerevisiae as a model, we quantitatively characterize intracellular RNA transport from mothers into their buds. Our results suggest that, at cytokinesis, ENO2 diSpinach RNA is preferentially distributed to daughters. This asymmetric RNA segregation depends on the lifespan regulator Sir2 and decreases with increasing replicative age of mothers but does not result from increasing cell size during aging. Overall, our approach opens more opportunities to study RNA dynamics and inheritance in live budding yeast at the single-cell level. AU - Kukhtevich, I. AU - Rivero-Romano, M. AU - Rakesh, N. AU - Bheda, P. AU - Chadha, Y. AU - Rosales-Becerra, P.* AU - Hamperl, S. AU - Bureik, D. AU - Dornauer, S. AU - Dargemont, C.* AU - Kirmizis, A.* AU - Schmoller, K.M. AU - Schneider, R. C1 - 66760 C2 - 53295 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Quantitative RNA imaging in single live cells reveals age-dependent asymmetric inheritance. JO - Cell Rep. VL - 41 IS - 7 PB - Cell Press PY - 2022 SN - 2211-1247 ER - TY - JOUR AB - Caloric restriction is a robust intervention to increase lifespan. Giving less food (calorie restriction [CR]) or allowing free access to a diluted diet with indigestible components (calorie dilution [CD]) are two methods to impose restriction. CD does not generate the same lifespan effect as CR. We compare responses of C57BL/6 mice with equivalent levels of CR and CD. The two groups have different responses in fat loss, circulating hormones, and metabolic rate. CR mice are hungrier, as assessed by behavioral assays. Although gene expression of Npy, Agrp, and Pomc do not differ between CR and CD groups, CR mice had a distinctive hypothalamic gene-expression profile with many genes related to starvation upregulated relative to CD. While both result in lower calorie intake, CR and CD are not equivalent procedures. Increased hunger under CR supports the hypothesis that hunger signaling is a key process mediating the benefits of CR. AU - Liu, X. AU - Jin, Z.* AU - Summers, S.* AU - Derous, D.* AU - Li, M.* AU - Li, B.* AU - Li, L.* AU - Speakman, J.R.* C1 - 65086 C2 - 52126 TI - Calorie restriction and calorie dilution have different impacts on body fat, metabolism, behavior, and hypothalamic gene expression. JO - Cell Rep. VL - 39 IS - 7 PY - 2022 SN - 2211-1247 ER - TY - JOUR AB - Ewing sarcoma (EwS) is characterized by EWSR1-ETS fusion transcription factors converting polymorphic GGAA microsatellites (mSats) into potent neo-enhancers. Although the paucity of additional mutations makes EwS a genuine model to study principles of cooperation between dominant fusion oncogenes and neo-enhancers, this is impeded by the limited number of well-characterized models. Here we present the Ewing Sarcoma Cell Line Atlas (ESCLA), comprising whole-genome, DNA methylation, transcriptome, proteome, and chromatin immunoprecipitation sequencing (ChIP-seq) data of 18 cell lines with inducible EWSR1-ETS knockdown. The ESCLA shows hundreds of EWSR1-ETS-targets, the nature of EWSR1-ETS-preferred GGAA mSats, and putative indirect modes of EWSR1-ETS-mediated gene regulation, converging in the duality of a specific but plastic EwS signature. We identify heterogeneously regulated EWSR1-ETS-targets as potential prognostic EwS biomarkers. Our freely available ESCLA (http://r2platform.com/escla/) is a rich resource for EwS research and highlights the power of comprehensive datasets to unravel principles of heterogeneous gene regulation by chimeric transcription factors. AU - Orth, M.F.* AU - Surdez, D.* AU - Faehling, T.* AU - Ehlers, A.C.* AU - Marchetto, A.* AU - Grossetete, S.* AU - Volckmann, R.* AU - Zwijnenburg, D.A.* AU - Gerke, J.S.* AU - Zaidi, S.* AU - Alonso, J.* AU - Sastre, A.* AU - Baulande, S.* AU - Sill, M.* AU - Cidre-Aranaz, F.* AU - Ohmura, S.* AU - Kirchner, T.* AU - Hauck, S.M. AU - Reischl, E. AU - Gymrek, M.* AU - Pfister, S.M.* AU - Strauch, K. AU - Koster, J.* AU - Delattre, O.* AU - Grunewald, T.G.P.* C1 - 66934 C2 - 53355 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Systematic multi-omics cell line profiling uncovers principles of Ewing sarcoma fusion oncogene-mediated gene regulation. JO - Cell Rep. VL - 41 IS - 10 PB - Cell Press PY - 2022 SN - 2211-1247 ER - TY - JOUR AB - The complexity of signaling events and cellular responses unfolding in neuronal, glial, and immune cells upon traumatic brain injury (TBI) constitutes an obstacle in elucidating pathophysiological links and targets for intervention. We use array phosphoproteomics in a murine mild blunt TBI to reconstruct the temporal dynamics of tyrosine-kinase signaling in TBI and then scrutinize the large-scale effects of perturbation of Met/HGFR, VEGFR1, and Btk signaling by small molecules. We show Met/HGFR as a selective modifier of early microglial response and that Met/HGFR blockade prevents the induction of microglial inflammatory mediators, of reactive microglia morphology, and TBI-associated responses in neurons and vasculature. Both acute and prolonged Met/HGFR inhibition ameliorate neuronal survival and motor recovery. Early elevation of HGF itself in the cerebrospinal fluid of TBI patients suggests that this mechanism has translational value in human subjects. Our findings identify Met/HGFR as a modulator of early neuroinflammation in TBI with promising translational potential. AU - Rehman, R.* AU - Miller, M.* AU - Krishnamurthy, S.S.* AU - Kjell, J. AU - Elsayed, L.* AU - Hauck, S.M. AU - olde Heuvel, F.* AU - Conquest, A.* AU - Chandrasekar, A.* AU - Ludolph, A.* AU - Boeckers, T.* AU - Mulaw, M.A.* AU - Götz, M. AU - Morganti-Kossmann, M.C.* AU - Takeoka, A.* AU - Roselli, F.* C1 - 67094 C2 - 53442 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Met/HGFR triggers detrimental reactive microglia in TBI. JO - Cell Rep. VL - 41 IS - 13 PB - Cell Press PY - 2022 SN - 2211-1247 ER - TY - JOUR AB - Ribosomopathies constitute a range of disorders associated with defective protein synthesis mainly affecting hematopoietic stem cells (HSCs) and erythroid development. Here, we demonstrate that deletion of poly-pyrimidine-tract-binding protein 1 (PTBP1) in the hematopoietic compartment leads to the development of a ribosomopathy-like condition. Specifically, loss of PTBP1 is associated with decreases in HSC self-renewal, erythroid differentiation, and protein synthesis. Consistent with its function as a splicing regulator, PTBP1 deficiency results in splicing defects in hundreds of genes, and we demonstrate that the up-regulation of a specific isoform of CDC42 partly mimics the protein-synthesis defect associated with loss of PTBP1. Furthermore, PTBP1 deficiency is associated with a marked defect in ribosome biogenesis and a selective reduction in the translation of mRNAs encoding ribosomal proteins. Collectively, this work identifies PTBP1 as a key integrator of ribosomal functions and highlights the broad functional repertoire of RNA-binding proteins. AU - Rehn, M.* AU - Wenzel, A.* AU - Frank, A.K.* AU - Schuster, M.B.* AU - Pundhir, S.* AU - Jørgensen, N.* AU - Vitting-Seerup, K.* AU - Ge, Y.* AU - Jendholm, J.* AU - Michaut, M.* AU - Schoof, E.M.* AU - Jensen, T.L.* AU - Rapin, N.* AU - Sapio, R.T.* AU - Andersen, K.L.* AU - Lund, A.H.* AU - Solimena, M. AU - Holzenberger, M.* AU - Pestov, D.G.* AU - Porse, B.T.* C1 - 64980 C2 - 52007 TI - PTBP1 promotes hematopoietic stem cell maintenance and red blood cell development by ensuring sufficient availability of ribosomal constituents. JO - Cell Rep. VL - 39 IS - 6 PY - 2022 SN - 2211-1247 ER - TY - JOUR AB - The sense of smell helps us navigate the environment, but its molecular architecture and underlying logic remain understudied. The spatial location of odorant receptor genes (Olfrs) in the nose is thought to be independent of the structural diversity of the odorants they detect. Using spatial transcriptomics, we create a genome-wide 3D atlas of the mouse olfactory mucosa (OM). Topographic maps of genes differentially expressed in space reveal that both Olfrs and non-Olfrs are distributed in a continuous and overlapping fashion over at least five broad zones in the OM. The spatial locations of Olfrs correlate with the mucus solubility of the odorants they recognize, providing direct evidence for the chromatographic theory of olfaction. This resource resolves the molecular architecture of the mouse OM and will inform future studies on mechanisms underlying Olfr gene choice, axonal pathfinding, patterning of the nervous system, and basic logic for the peripheral representation of smell. AU - Ruiz Tejada Segura, M.L. AU - Abou Moussa, E.* AU - Garabello, E. AU - Nakahara, T.S.* AU - Makhlouf, M.* AU - Mathew, L.S.* AU - Wang, L.* AU - Valle, F.* AU - Huang, S.S.Y.* AU - Mainland, J.D.* AU - Caselle, M.* AU - Osella, M.* AU - Lorenz, S.* AU - Reisert, J.* AU - Logan, D.W.* AU - Malnic, B.* AU - Scialdone, A. AU - Saraiva, L.R.* C1 - 64679 C2 - 51973 TI - A 3D transcriptomics atlas of the mouse nose sheds light on the anatomical logic of smell. JO - Cell Rep. VL - 38 IS - 12 PY - 2022 SN - 2211-1247 ER - TY - JOUR AB - Survival or apoptosis is a binary decision in individual cells. However, at the cell-population level, a graded increase in survival of colony-forming unit-erythroid (CFU-E) cells is observed upon stimulation with erythropoietin (Epo). To identify components of Janus kinase 2/signal transducer and activator of transcription 5 (JAK2/STAT5) signal transduction that contribute to the graded population response, we extended a cell-population-level model calibrated with experimental data to study the behavior in single cells. The single-cell model shows that the high cell-to-cell variability in nuclear phosphorylated STAT5 is caused by variability in the amount of Epo receptor (EpoR):JAK2 complexes and of SHP1, as well as the extent of nuclear import because of the large variance in the cytoplasmic volume of CFU-E cells. 24–118 pSTAT5 molecules in the nucleus for 120 min are sufficient to ensure cell survival. Thus, variability in membrane-associated processes is sufficient to convert a switch-like behavior at the single-cell level to a graded population-level response. AU - Adlung, L.* AU - Stapor, P. AU - Tönsing, C.* AU - Schmiester, L. AU - Schwarzmüller, L.E.* AU - Postawa, L.* AU - Wang, D. AU - Timmer, J.* AU - Klingmüller, U.* AU - Hasenauer, J. AU - Schilling, M.* C1 - 62798 C2 - 51068 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Cell-to-cell variability in JAK2/STAT5 pathway components and cytoplasmic volumes defines survival threshold in erythroid progenitor cells. JO - Cell Rep. VL - 36 IS - 6 PB - Cell Press PY - 2021 SN - 2211-1247 ER - TY - JOUR AB - Gut microbiota have been shown to promote oogenesis and fecundity, but the mechanistic basis of remote influence on oogenesis remained unknown. Here, we report a systemic mechanism of influence mediated by bacterial-derived supply of mitochondrial coenzymes. Removal of microbiota decreased mitochondrial activity and ATP levels in the whole-body and ovary, resulting in repressed oogenesis. Similar repression was caused by RNA-based knockdown of mitochondrial function in ovarian follicle cells. Reduced mitochondrial function in germ-free (GF) females was reversed by bacterial recolonization or supplementation of riboflavin, a precursor of FAD and FMN. Metabolomics analysis of GF females revealed a decrease in oxidative phosphorylation and FAD levels and an increase in metabolites that are degraded by FAD-dependent enzymes (e.g., amino and fatty acids). Riboflavin supplementation opposed this effect, elevating mitochondrial function, ATP, and oogenesis. These findings uncover a bacterial-mitochondrial axis of influence, linking gut bacteria with systemic regulation of host energy and reproduction. AU - Gnainsky, Y.* AU - Zfanya, N.* AU - Elgart, M.* AU - Omri, E.* AU - Brandis, A.* AU - Mehlman, T.* AU - Itkin, M.* AU - Malitsky, S.* AU - Adamski, J. AU - Soen, Y.* C1 - 61012 C2 - 50007 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Systemic regulation of host energy and oogenesis by microbiome-derived mitochondrial coenzymes. JO - Cell Rep. VL - 34 IS - 1 PB - Cell Press PY - 2021 SN - 2211-1247 ER - TY - JOUR AB - Glioblastoma multiforme (GBM) possesses glioma stem cells (GSCs) that promote self-renewal, tumor propagation, and relapse. Understanding the mechanisms of GSCs self-renewal can offer targeted therapeutic interventions. However, insufficient knowledge of GSCs' fundamental biology is a significant bottleneck hindering these efforts. Here, we show that patient-derived GSCs recruit elevated levels of proteins that ensure the temporal cilium disassembly, leading to suppressed ciliogenesis. Depleting the cilia disassembly complex components is sufficient to induce ciliogenesis in a subset of GSCs via relocating platelet-derived growth factor receptor-alpha (PDGFR-α) to a newly induced cilium. Importantly, restoring ciliogenesis enabled GSCs to switch from self-renewal to differentiation. Finally, using an organoid-based glioma invasion assay and brain xenografts in mice, we establish that ciliogenesis-induced differentiation can prevent the infiltration of GSCs into the brain. Our findings illustrate a role for cilium as a molecular switch in determining GSCs' fate and suggest cilium induction as an attractive strategy to intervene in GSCs proliferation. AU - Goranci-Buzhala, G.* AU - Mariappan, A.* AU - Ricci-Vitiani, L.* AU - Josipovic, N.* AU - Pacioni, S.* AU - Gottardo, M.* AU - Ptok, J.* AU - Schaal, H.* AU - Callaini, G.* AU - Rajalingam, K.* AU - Dynlacht, B.D.* AU - Hadian, K. AU - Papantonis, A.* AU - Pallini, R.* AU - Gopalakrishnan, J.* C1 - 62944 C2 - 51204 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Cilium induction triggers differentiation of glioma stem cells. JO - Cell Rep. VL - 36 IS - 10 PB - Cell Press PY - 2021 SN - 2211-1247 ER - TY - JOUR AB - The Authors Glucocorticoids such as dexamethasone are widely used immunomodulators. Combining proteomics, ChIP-seq, RNA-seq, and genetic loss-of-function studies in murine macrophages, Greulich et al. show that recruitment of the SETD1A/COMPASS complex to cis-regulatory elements by the glucocorticoid receptor mediates some of their anti-inflammatory actions. AU - Greulich, F. AU - Wierer, M.* AU - Mechtidou, A. AU - Gonzalez-Garcia, O. AU - Uhlenhaut, N.H. C1 - 61300 C2 - 50114 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - The glucocorticoid receptor recruits the COMPASS complex to regulate inflammatory transcription at macrophage enhancers. JO - Cell Rep. VL - 34 IS - 6 PB - Cell Press PY - 2021 SN - 2211-1247 ER - TY - JOUR AB - The basal ganglia (BG) are a group of subcortical nuclei responsible for motor and executive function. Central to BG function are striatal cells expressing D1 (D1R) and D2 (D2R) dopamine receptors. D1R and D2R cells are considered functional antagonists that facilitate voluntary movements and inhibit competing motor patterns, respectively. However, whether they maintain a uniform function across the striatum and what influence they exert outside the BG is unclear. Here, we address these questions by combining optogenetic activation of D1R and D2R cells in the mouse ventrolateral caudoputamen with fMRI. Striatal D1R/D2R stimulation evokes distinct activity within the BG-thalamocortical network and differentially engages cerebellar and prefrontal regions. Computational modeling of effective connectivity confirms that changes in D1R/D2R output drive functional relationships between these regions. Our results suggest a complex functional organization of striatal D1R/D2R cells and hint toward an interconnected fronto-BG-cerebellar network modulated by striatal D1R and D2R cells. AU - Grimm, C.* AU - Frässle, S.* AU - Steger, C.* AU - von Ziegler, L.* AU - Sturman, O.* AU - Shemesh, N.* AU - Peleg-Raibstein, D.* AU - Burdakov, D.* AU - Bohacek, J.* AU - Stephan, K.E.* AU - Razansky, D. AU - Wenderoth, N.* AU - Zerbi, V.* C1 - 63929 C2 - 51666 TI - Optogenetic activation of striatal D1R and D2R cells differentially engages downstream connected areas beyond the basal ganglia. JO - Cell Rep. VL - 37 IS - 13 PY - 2021 SN - 2211-1247 ER - TY - JOUR AB - Using chromatin conformation capture, we show that an enhancer cluster in the STARD10 type 2 diabetes (T2D) locus forms a defined 3-dimensional (3D) chromatin domain. A 4.1-kb region within this locus, carrying 5 T2D-associated variants, physically interacts with CTCF-binding regions and with an enhancer possessing strong transcriptional activity. Analysis of human islet 3D chromatin interaction maps identifies the FCHSD2 gene as an additional target of the enhancer cluster. CRISPR-Cas9-mediated deletion of the variant region, or of the associated enhancer, from human pancreas-derived EndoC-βH1 cells impairs glucose-stimulated insulin secretion. Expression of both STARD10 and FCHSD2 is reduced in cells harboring CRISPR deletions, and lower expression of STARD10 and FCHSD2 is associated, the latter nominally, with the possession of risk variant alleles in human islets. Finally, CRISPR-Cas9-mediated loss of STARD10 or FCHSD2, but not ARAP1, impairs regulated insulin secretion. Thus, multiple genes at the STARD10 locus influence β cell function. AU - Hu, M.* AU - Cebola, I.* AU - Carrat, G.* AU - Jiang, S.* AU - Nawaz, S.* AU - Khamis, A.* AU - Canouil, M.* AU - Froguel, P.* AU - Schulte, A.* AU - Solimena, M. AU - Ibberson, M.* AU - Marchetti, P.* AU - Cardenas-Diaz, F.L.* AU - Gadue, P.J.* AU - Hastoy, B.* AU - Alemeida-Souza, L.* AU - McMahon, H.* AU - Rutter, G.A.* C1 - 61182 C2 - 50073 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a regulator of insulin secretion. JO - Cell Rep. VL - 34 IS - 5 PB - Cell Press PY - 2021 SN - 2211-1247 ER - TY - JOUR AB - Astrocytes are a viable source for generating new neurons via direct conversion. However, little is known about the neurogenic cascades triggered in astrocytes from different regions of the CNS. Here, we examine the transcriptome induced by the proneural factors Ascl1 and Neurog2 in spinal cord-derived astrocytes in vitro. Each factor initially elicits different neurogenic programs that later converge to a V2 interneuron-like state. Intriguingly, patch sequencing (patch-seq) shows no overall correlation between functional properties and the transcriptome of the heterogenous induced neurons, except for K-channels. For example, some neurons with fully mature electrophysiological properties still express astrocyte genes, thus calling for careful molecular and functional analysis. Comparing the transcriptomes of spinal cord- and cerebral-cortex-derived astrocytes reveals profound differences, including developmental patterning cues maintained in vitro. These relate to the distinct neuronal identity elicited by Ascl1 and Neurog2 reflecting their developmental functions in subtype specification of the respective CNS region. AU - Kempf, J.* AU - Knelles, K.* AU - Hersbach, B.A.* AU - Petrik, D. AU - Riedemann, T.* AU - Bednarova, V.* AU - Janjic, A.* AU - Simon-Ebert, T.* AU - Enard, W.* AU - Smialowski, P. AU - Götz, M. AU - Masserdotti, G. C1 - 62645 C2 - 50970 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Heterogeneity of neurons reprogrammed from spinal cord astrocytes by the proneural factors Ascl1 and Neurogenin2. JO - Cell Rep. VL - 36 IS - 3 PB - Cell Press PY - 2021 SN - 2211-1247 ER - TY - JOUR AB - Maintaining organelle function in the face of stress is known to involve organelle-specific retrograde signaling. Using Caenorhabditis elegans, we present evidence of the existence of such retrograde signaling for peroxisomes, which we define as the peroxisomal retrograde signaling (PRS). Specifically, we show that peroxisomal import stress caused by knockdown of the peroxisomal matrix import receptor prx-5/PEX5 triggers NHR-49/peroxisome proliferator activated receptor alpha (PPARα)- and MDT-15/MED15-dependent upregulation of the peroxisomal Lon protease lonp-2/LONP2 and the peroxisomal catalase ctl-2/CAT. Using proteomic and transcriptomic analyses, we show that proteins involved in peroxisomal lipid metabolism and immunity are also upregulated upon prx-5(RNAi). While the PRS can be triggered by perturbation of peroxisomal β-oxidation, we also observed hallmarks of PRS activation upon infection with Pseudomonas aeruginosa. We propose that the PRS, in addition to a role in lipid metabolism homeostasis, may act as a surveillance mechanism to protect against pathogens. AU - Rackles, E.* AU - Witting,M. AU - Forné, I.* AU - Zhang, X.* AU - Zacherl, J.* AU - Schrott, S.* AU - Fischer, C.* AU - Ewbank, J.J.* AU - Osman, C.* AU - Imhof, A.* AU - Rolland, S.G.* C1 - 61077 C2 - 50036 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Reduced peroxisomal import triggers peroxisomal retrograde signaling. JO - Cell Rep. VL - 34 IS - 3 PB - Cell Press PY - 2021 SN - 2211-1247 ER - TY - JOUR AB - Thermoneutral conditions typical for standard human living environments result in brown adipose tissue (BAT) involution, characterized by decreased mitochondrial mass and increased lipid deposition. Low BAT activity is associated with poor metabolic health, and BAT reactivation may confer therapeutic potential. However, the molecular drivers of this BAT adaptive process in response to thermoneutrality remain enigmatic. Using metabolic and lipidomic approaches, we show that endogenous fatty acid synthesis, regulated by carbohydrate-response element-binding protein (ChREBP), is the central regulator of BAT involution. By transcriptional control of lipogenesis-related enzymes, ChREBP determines the abundance and composition of both storage and membrane lipids known to regulate organelle turnover and function. Notably, ChREBP deficiency and pharmacological inhibition of lipogenesis during thermoneutral adaptation preserved mitochondrial mass and thermogenic capacity of BAT independently of mitochondrial biogenesis. In conclusion, we establish lipogenesis as a potential therapeutic target to prevent loss of BAT thermogenic capacity as seen in adult humans. AU - Schlein, C.* AU - Fischer, A.W.* AU - Sass, F.* AU - Worthmann, A.* AU - Tödter, K.* AU - Jaeckstein, M.Y.* AU - Behrens, J.* AU - Lynes, M.D.* AU - Kiebish, M.A.* AU - Narain, N.R.* AU - Bussberg, V.* AU - Darkwah, A.* AU - Jespersen, N.Z.* AU - Nielsen, S.* AU - Scheele, C.* AU - Schweizer, M.* AU - Braren, I.* AU - Bartelt, A. AU - Tseng, Y.H.* AU - Heeren, J.* AU - Scheja, L.* C1 - 61006 C2 - 50013 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Endogenous fatty acid synthesis drives brown adipose tissue involution. JO - Cell Rep. VL - 34 IS - 2 PB - Cell Press PY - 2021 SN - 2211-1247 ER - TY - JOUR AB - Brown adipose tissue (BAT) thermogenic activity is tightly regulated by cellular redox status, but the underlying molecular mechanisms are incompletely understood. Protein S-nitrosylation, the nitric-oxide-mediated cysteine thiol protein modification, plays important roles in cellular redox regulation. Here we show that diet-induced obesity (DIO) and acute cold exposure elevate BAT protein S-nitrosylation, including UCP1. This thermogenic-induced nitric oxide bioactivity is regulated by S-nitrosoglutathione reductase (GSNOR; alcohol dehydrogenase 5 [ADH5]), a denitrosylase that balances the intracellular nitroso-redox status. Loss of ADH5 in BAT impairs cold-induced UCP1-dependent thermogenesis and worsens obesity-associated metabolic dysfunction. Mechanistically, we demonstrate that Adh5 expression is induced by the transcription factor heat shock factor 1 (HSF1), and administration of an HSF1 activator to BAT of DIO mice increases Adh5 expression and significantly improves UCP1-mediated respiration. Together, these data indicate that ADH5 controls BAT nitroso-redox homeostasis to regulate adipose thermogenesis, which may be therapeutically targeted to improve metabolic health. AU - Sebag, S.C.* AU - Zhang, Z.* AU - Qian, Q.* AU - Li, M.* AU - Zhu, Z.* AU - Harata, M.* AU - Li, W.* AU - Zingman, L.V.* AU - Liu, L.* AU - Lira, V.A.* AU - Potthoff, M.J.* AU - Bartelt, A. AU - Yang, L.* C1 - 63645 C2 - 51506 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - ADH5-mediated NO bioactivity maintains metabolic homeostasis in brown adipose tissue. JO - Cell Rep. VL - 37 IS - 7 PB - Cell Press PY - 2021 SN - 2211-1247 ER - TY - JOUR AB - Acute myeloid leukemia (AML) is a rapidly progressing cancer, for which chemotherapy remains standard treatment and additional therapeutic targets are requisite. Here, we show that AML cells secrete the stem cell growth factor R-spondin 2 (RSPO2) to promote their self-renewal and prevent cell differentiation. Although RSPO2 is a well-known WNT agonist, we reveal that it maintains AML self-renewal WNT independently, by inhibiting BMP receptor signaling. Autocrine RSPO2 signaling is also required to prevent differentiation and to promote self-renewal in normal hematopoietic stem cells as well as primary AML cells. Comprehensive datamining reveals that RSPO2 expression is elevated in patients with AML of poor prognosis. Consistently, inhibiting RSPO2 prolongs survival in AML mouse xenograft models. Our study indicates that in AML, RSPO2 acts as an autocrine BMP antagonist to promote cancer cell renewal and may serve as a marker for poor prognosis. AU - Sun, R.* AU - He, L.* AU - Lee, H.* AU - Glinka, A.* AU - Andrésen, C.* AU - Hübschmann, D.* AU - Jeremias, I. AU - Müller-Decker, K.* AU - Pabst, C.* AU - Niehrs, C.* C1 - 62826 C2 - 51082 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - RSPO2 inhibits BMP signaling to promote self-renewal in acute myeloid leukemia. JO - Cell Rep. VL - 36 IS - 7 PB - Cell Press PY - 2021 SN - 2211-1247 ER - TY - JOUR AB - In a system with regulatable antigen presentation in vivo, Trefzer et al. find TCR signaling, gene transcription, and functionalities reversibly regulated by dose and time of chronically persisting antigen. Comparisons with naturally anergic and tumor-infiltrating T cells suggest that signatures of anergy and exhaustion by antigen largely overlap. AU - Trefzer, A.* AU - Kadam, P.* AU - Wang, S.H.* AU - Pennavaria, S.* AU - Lober, B.* AU - Akçabozan, B.* AU - Kranich, J.* AU - Brocker, T.* AU - Nakano, N.* AU - Irmler, M. AU - Beckers, J. AU - Straub, T.* AU - Obst, R.* C1 - 61298 C2 - 49791 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Dynamic adoption of anergy by antigen-exhausted CD4+ T cells. JO - Cell Rep. VL - 34 IS - 6 PB - Cell Press PY - 2021 SN - 2211-1247 ER - TY - JOUR AB - Extensive remodeling of the airways is a major characteristic of chronic inflammatory lung diseases such as asthma or chronic obstructive pulmonary disease (COPD). To elucidate the importance of a deregulated immune response in the airways for remodeling processes, we established a matching Drosophila model. Here, triggering the Imd (immune deficiency) pathway in tracheal cells induced organ-wide remodeling. This structural remodeling comprises disorganization of epithelial structures and comprehensive epithelial thickening. We show that these structural changes do not depend on the Imd pathway's canonical branch terminating on nuclear factor κB (NF-κB) activation. Instead, activation of a different segment of the Imd pathway that branches off downstream of Tak1 and comprises activation of c-Jun N-terminal kinase (JNK) and forkhead transcription factor of the O subgroup (FoxO) signaling is necessary and sufficient to mediate the observed structural changes of the airways. Our findings imply that targeting JNK and FoxO signaling in the airways could be a promising strategy to interfere with disease-associated airway remodeling processes. AU - Wagner, C.* AU - Uliczka, K.* AU - Bossen, J.* AU - Niu, X.* AU - Fink, C.* AU - Thiedmann, M.* AU - Knop, M.* AU - Vock, C.* AU - Abdelsadik, A.* AU - Zissler, U.M. AU - Isermann, K.* AU - Garn, H.* AU - Pieper, M.* AU - Wegmann, M.* AU - Koczulla, A.R.* AU - Vogelmeier, C.F.* AU - Schmidt-Weber, C.B. AU - Fehrenbach, H.* AU - König, P.* AU - Silverman, N.* AU - Renz, H.* AU - Pfefferle, P.I.* AU - Heine, H.* AU - Roeder, T.* C1 - 61794 C2 - 50461 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Constitutive immune activity promotes JNK- and FoxO-dependent remodeling of Drosophila airways. JO - Cell Rep. VL - 35 IS - 1 PB - Cell Press PY - 2021 SN - 2211-1247 ER - TY - JOUR AB - Chromatin states must be maintained during cell proliferation to uphold cellular identity and genome integrity. Inheritance of histone modifications is central in this process. However, the histone modification landscape is challenged by incorporation of new unmodified histones during each cell cycle, and the principles governing heritability remain unclear. We take a quantitative computational modeling approach to describe propagation of histone H3K27 and H3K36 methylation states. We measure combinatorial H3K27 and H3K36 methylation patterns by quantitative mass spectrometry on subsequent generations of histones. Using model comparison, we reject active global demethylation and invoke the existence of domains defined by distinct methylation endpoints. We find that H3K27me3 on pre-existing histones stimulates the rate of de novo H3K27me3 establishment, supporting a read-write mechanism in timely chromatin restoration. Finally, we provide a detailed quantitative picture of the mutual antagonism between H3K27 and H3K36 methylation and propose that it stabilizes epigenetic states across cell division. AU - Alabert, C.* AU - Loos, C. AU - Voelker-Albert, M.* AU - Graziano, S.* AU - Forné, I.* AU - Reveron-Gomez, N.* AU - Schuh, L. AU - Hasenauer, J. AU - Marr, C. AU - Imhof, A.* AU - Groth, A.* C1 - 58731 C2 - 48264 SP - 1223-1234 TI - Domain model explains propagation dynamics and stability of histone H3K27 and H3K36 methylation landscapes. JO - Cell Rep. VL - 30 IS - 4 PY - 2020 SN - 2211-1247 ER - TY - JOUR AB - Tumor cells orchestrate their microenvironment. Here, we provide biochemical, structural, functional, and clinical evidence that Cathepsin S (CTSS) alterations induce a tumor-promoting immune microenvironment in follicular lymphoma (FL). We found CTSS mutations at Y132 in 6% of FL (19/305). Another 13% (37/286) had CTSS amplification, which was associated with higher CTSS expression. CTSS Y132 mutations lead to accelerated autocatalytic conversion from an enzymatically inactive profrom to active CTSS and increased substrate cleavage, including CD74, which regulates major histocompatibility complex class II (MHC class II)-restricted antigen presentation. Lymphoma cells with hyperactive CTSS more efficiently activated antigen-specific CD4(+) T cells in vitro, Tumors with hyperactive CTSS showed increased CD4(+) T cell infiltration and proinflammatory cytokine perturbation in a mouse model and in human FLs. In mice, this CTSS-induced immune microenvironment promoted tumor growth. Clinically, patients with CTSS-hyperactive FL had better treatment outcomes with standard immunochemotherapies, indicating that these immunosuppressive regimens target both the lymphoma cells and the tumor-promoting immune microenvironment. AU - Bararia, D.* AU - Hildebrand, J.A.* AU - Stolz, S.* AU - Haebe, S.* AU - Alig, S.* AU - Trevisani, C.P.* AU - Osorio-Barrios, F.* AU - Bartoschek, M.D.* AU - Mentz, M.* AU - Pastore, A.* AU - Gaitzsch, E.* AU - Heide, M.* AU - Jurinovic, V.* AU - Rautter, K. AU - Gunawardana, J.* AU - Sabdia, M.B.* AU - Szczepanowski, M.* AU - Richter, J.* AU - Klapper, W.* AU - Louissaint, A.* AU - Ludwig, C.* AU - Bultmann, S.* AU - Leonhardt, H.* AU - Eustermann, S.* AU - Hopfner, K.P.* AU - Hiddemann, W.* AU - von Bergwelt-Baildon, M.* AU - Steidl, C.* AU - Kridel, R.* AU - Tobin, J.W.D.* AU - Gandhi, M.K.* AU - Weinstock, D.M.* AU - Schmidt-Supprian, M.* AU - Sárosi, M.B.* AU - Rudelius, M.* AU - Passerini, V.* AU - Mautner, J. AU - Weigert, O.* C1 - 59053 C2 - 48611 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Cathepsin S alterations induce a tumor-promoting immune microenvironment in follicular lymphoma. JO - Cell Rep. VL - 31 IS - 5 PB - Cell Press PY - 2020 SN - 2211-1247 ER - TY - JOUR AB - Type 2 diabetes is characterized by peripheral insulin resistance and insufficient insulin release from pancreatic islet beta cells. However, the role and sequence of b cell dysfunction and mass loss for reduced insulin levels in type 2 diabetes pathogenesis are unclear. Here, we exploit freshly explanted pancreas specimens from metabolically phenotyped surgical patients using an in situ tissue slice technology. This approach allows assessment of beta cell volume and function within pancreas samples of metabolically stratified individuals. We show that, in tissue of pre-diabetic, impaired glucose-tolerant subjects, beta cell volume is unchanged, but function significantly deteriorates, exhibiting increased basal release and loss of first-phase insulin secretion. In individuals with type 2 diabetes, function within the sustained beta cell volume further declines. These results indicate that dysfunction of persisting beta cells is a key factor in the early development and progression of type 2 diabetes, representing a major target for diabetes prevention and therapy. AU - Cohrs, C.M. AU - Panzer, J.K. AU - Drotar, D.M. AU - Enos, S.J. AU - Kipke, N. AU - Chen, C. AU - Schöniger, E. AU - Ehehalt, F.* AU - Distler, M.* AU - Brennand, A.* AU - Bornstein, S.R. AU - Weitz, J. AU - Solimena, M. AU - Speier, S. C1 - 58825 C2 - 48456 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Dysfunction of persisting β cells is a key feature of early type 2 diabetes pathogenesis. JO - Cell Rep. VL - 31 IS - 1 PB - Cell Press PY - 2020 SN - 2211-1247 ER - TY - JOUR AB - Biofluids contain various circulating cell-free RNAs (ccfRNAs). The composition of these ccfRNAs varies among biofluids. They constitute tantalizing biomarker candidates for several pathologies and have been demonstrated to be mediators of cellular communication. Little is known about their function in physiological and developmental settings, and most works are limited to in vitro studies. Here, we develop iTAG-RNA, a method for the unbiased tagging of RNA transcripts in mice in vivo. We use iTAG-RNA to isolate hepatocytes and kidney proximal epithelial cell-specific transcriptional responses to a dietary challenge without interfering with the tissue architecture and to identify multiple hepatocyte-secreted ccfRNAs in plasma. We also identify specific transfer of liver-derived ccfRNAs to adipose tissue and skeletal muscle, where they likely constitute a buffering system to maintain lipid homeostasis under acute high-fat-diet feeding. Our findings directly demonstrate in vivo transfer of RNAs between tissues and highlight its implications for endocrine signaling and homeostasis. AU - Darr, J. AU - Tomar, A. AU - Lassi, M. AU - Gerlini, R. AU - Berti, L. AU - Hering, A. AU - Scheid, F. AU - Hrabě de Angelis, M. AU - Witting, M. AU - Teperino, R. C1 - 58526 C2 - 48131 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 3183-3194.e4 TI - iTAG-RNA isolates cell-specific transcriptional responses to environmental stimuli and identifies an RNA-based endocrine axis. JO - Cell Rep. VL - 30 IS - 9 PB - Cell Press PY - 2020 SN - 2211-1247 ER - TY - JOUR AB - Ferroptosis is a type of regulated cell death driven by the iron-dependent accumulation of oxidized polyunsaturated fatty acid-containing phospholipids. There is no reliable way to selectively stain ferroptotic cells in tissue sections to characterize the extent of ferroptosis in animal models or patient samples. We address this gap by immunizing mice with membranes from lymphoma cells treated with the ferroptosis inducer piperazine erastin and screening similar to 4,750 of the resulting monoclonal antibodies generated for their ability to selectively detect cells undergoing ferroptosis. We find that one antibody, 3F3 ferroptotic membrane antibody (3F3-FMA), is effective as a selective ferroptosis-staining reagent. The antigen of 3F3-FMA is identified as the human transferrin receptor 1 protein (TfR1). We validate this finding with several additional anti-TfR1 antibodies and compare them to other potential ferroptosis-detecting reagents. We find that anti-TfR1 and anti-malondialdehyde adduct antibodies are effective at staining ferroptotic tumor cells in multiple cell culture and tissue contexts. AU - Feng, H.* AU - Schorpp, K.K. AU - Jin, J.* AU - Yozwiak, C.E.* AU - Hoffstrom, B.G.* AU - Decker, A.M.* AU - Rajbhandari, P.* AU - Stokes, M.E.* AU - Bender, H.G.* AU - Csuka, J.M.* AU - Upadhyayula, P.S.* AU - Canoll, P.* AU - Uchida, K.* AU - Soni, R.K.* AU - Hadian, K. AU - Stockwell, B.R.* C1 - 58571 C2 - 48375 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 3411-3423.e7 TI - Transferrin receptor is a specific ferroptosis marker. JO - Cell Rep. VL - 30 IS - 10 PB - Cell Press PY - 2020 SN - 2211-1247 ER - TY - JOUR AB - Extracellular RNAs present in biofluids have emerged as potential biomarkers for disease. Where most studies focus on blood-derived fluids, other biofluids may be more informative. We present an atlas of messenger, circular, and small RNA transcriptomes of a comprehensive collection of 20 human biofluids. By means of synthetic spike-in controls, we compare RNA content across biofluids, revealing a 10,000-fold difference in concentration. The circular RNA fraction is increased in most biofluids compared to tissues. Each biofluid transcriptome is enriched for RNA molecules derived from specific tissues and cell types. Our atlas enables an informed selection of the most relevant biofluid to monitor particular diseases. To verify the biomarker potential in these biofluids, four validation cohorts representing a broad spectrum of diseases were profiled, revealing numerous differential RNAs between case and control subjects. Spike-normalized data are publicly available in the R2 web portal for further exploration. AU - Hulstaert, E.* AU - Morlion, A.* AU - Avila Cobos, F.* AU - Verniers, K.* AU - Nuytens, J.* AU - Vanden Eynde, E.* AU - Yigit, N.* AU - Anckaert, J.* AU - Geerts, A.* AU - Hindryckx, P.* AU - Jacques, P.* AU - Brusselle, G.* AU - Bracke, K.R.* AU - Maes, T.* AU - Malfait, T.* AU - Derveaux, T.* AU - Ninclaus, V.* AU - Van Cauwenbergh, C.* AU - Roelens, K.* AU - Roets, E.* AU - Hemelsoet, D.* AU - Tilleman, K.* AU - Brochez, L.* AU - Kuersten, S.* AU - Simon, L.M.* AU - Karg, S. AU - Kautzky-Willers, A.* AU - Leutner, M.* AU - Nöhammer, C.* AU - Slaby, O.* AU - Prins, R.W.* AU - Koster, J.* AU - Lefever, S.* AU - Schroth, G.P.* AU - Vandesompele, J.* AU - Mestdagh, P.* C1 - 60908 C2 - 49744 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Charting extracellular transcriptomes in the Human Biofluid RNA Atlas. JO - Cell Rep. VL - 33 IS - 13 PB - Cell Press PY - 2020 SN - 2211-1247 ER - TY - JOUR AB - TMEM18 is the strongest candidate for childhood obesity identified from GWASs, yet as for most GWAS-derived obesity-susceptibility genes, the functional mechanism remains elusive. We here investigate the relevance of TMEM18 for adipose tissue development and obesity. We demonstrate that adipocyte TMEM18 expression is downregulated in children with obesity. Functionally, downregulation of TMEM18 impairs adipocyte formation in zebrafish and in human preadipocytes, indicating that TMEM18 is important for adipocyte differentiation in vivo and in vitro. On the molecular level, TMEM1 8 activates PPARG, particularly upregulating PPARG1 promoter activity, and this activation is repressed by inflammatory stimuli. The relationship between TMEM18 and PPARG1 is also evident in adipocytes of children and is clinically associated with obesity and adipocyte hypertrophy, inflammation, and insulin resistance. Our findings indicate a role of TMEM18 as an upstream regulator of PPARG signaling driving healthy adipogenesis, which is dysregulated with adipose tissue dysfunction and obesity. AU - Landgraf, K.* AU - Klöting, N. AU - Gericke, M.* AU - Maixner, N.* AU - Guiu-Jurado, E.* AU - Scholz, M.* AU - Witte, A.V.* AU - Beyer, F.* AU - Schwartze, J.T.* AU - Lacher, M.* AU - Villringer, A.* AU - Kovacs, P.* AU - Rudich, A.* AU - Blüher, M. AU - Kiess, W.* AU - Körner, A.* C1 - 60365 C2 - 49186 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - The obesity susceptibility gene TMEM18 promotes adipogenesis through direct activation of PPARG. JO - Cell Rep. VL - 33 IS - 3 PB - Cell Press PY - 2020 SN - 2211-1247 ER - TY - JOUR AB - Genetic variations in TMEM106B, coding for a lysosomal membrane protein, affect frontotemporal lobar degeneration (FTLD) in GRN- (coding for progranulin) and C9orf72-expansion carriers and might play a role in aging. To determine the physiological function of TMEM106B, we generated TMEM106B-deficient mice. These mice develop proximal axonal swellings caused by drastically enlarged LAMP1-positive vacuoles, increased retrograde axonal transport of lysosomes, and accumulation of lipofuscin and autophagosomes. Giant vacuoles specifically accumulate at the distal end and within the axon initial segment, but not in peripheral nerves or at axon terminals, resulting in an impaired facial-nerve-dependent motor performance. These data implicate TMEM106B in mediating the axonal transport of LAMP1-positive organelles in motoneurons and axonal sorting at the initial segment. Our data provide mechanistic insight into how TMEM106B affects lysosomal proteolysis and degradative capacity in neurons. AU - Lüningschrör, P.* AU - Werner, G.* AU - Stroobants, S.* AU - Kakuta, S.* AU - Dombert, B.* AU - Sinske, D.* AU - Wanner, R.* AU - Lüllmann-Rauch, R.* AU - Wefers, B. AU - Wurst, W. AU - D'Hooge, R.* AU - Uchiyama, Y.* AU - Sendtner, M.* AU - Haass, C.* AU - Saftig, P.* AU - Knöll, B.* AU - Capell, A.* AU - Damme, M.* C1 - 58570 C2 - 48374 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 3506-3519.e6 TI - The FTLD risk factor TMEM106B regulates the transport of lysosomes at the axon initial segment of motoneurons. JO - Cell Rep. VL - 30 IS - 10 PB - Cell Press PY - 2020 SN - 2211-1247 ER - TY - JOUR AB - Pancreatic β cell failure is key to type 2 diabetes (T2D) onset and progression. Here, we assess whether human β cell dysfunction induced by metabolic stress is reversible, evaluate the molecular pathways underlying persistent or transient damage, and explore the relationships with T2D islet traits. Twenty-six islet preparations are exposed to several lipotoxic/glucotoxic conditions, some of which impair insulin release, depending on stressor type, concentration, and combination. The reversal of dysfunction occurs after washout for some, although not all, of the lipoglucotoxic insults. Islet transcriptomes assessed by RNA sequencing and expression quantitative trait loci (eQTL) analysis identify specific pathways underlying β cell failure and recovery. Comparison of a large number of human T2D islet transcriptomes with those of persistent or reversible β cell lipoglucotoxicity show shared gene expression signatures. The identification of mechanisms associated with human β cell dysfunction and recovery and their overlap with T2D islet traits provide insights into T2D pathogenesis, fostering the development of improved β cell-targeted therapeutic strategies. AU - Marselli, L.* AU - Piron, A.* AU - Suleiman, M.* AU - Colli, M.L.* AU - Yi, X.* AU - Khamis, A.* AU - Carrat, G.R.* AU - Rutter, G.A.* AU - Bugliani, M.* AU - Giusti, L.* AU - Ronci, M.* AU - Ibberson, M.* AU - Turatsinze, J.V.* AU - Boggi, U.* AU - De Simone, P.* AU - De Tata, V.* AU - Lopes, M.* AU - Nasteska, D.* AU - De Luca, C.* AU - Tesi, M.* AU - Bosi, E.* AU - Singh, P.* AU - Campani, D.* AU - Schulte, A.M.* AU - Solimena, M. AU - Hecht, P.* AU - Rady, B.* AU - Bakaj, I.* AU - Pocai, A.* AU - Norquay, L.* AU - Thorens, B.* AU - Canouil, M.* AU - Froguel, P.* AU - Eizirik, D.L.* AU - Cnop, M.* AU - Marchetti, P.* C1 - 60717 C2 - 49588 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Persistent or transient human β cell dysfunction induced by metabolic stress: Specific signatures and shared gene expression with type 2 diabetes. JO - Cell Rep. VL - 33 IS - 9 PB - Cell Press PY - 2020 SN - 2211-1247 ER - TY - JOUR AB - The proteasome is the main proteolytic system for targeted protein degradation in the cell and is fine-tuned according to cellular needs. Here, we demonstrate that mitochondrial dysfunction and concomitant metabolic reprogramming of the tricarboxylic acid (TCA) cycle reduce the assembly and activity of the 26S proteasome. Both mitochondrial mutations in respiratory complex I and treatment with the anti-diabetic drug metformin impair 26S proteasome activity. Defective 26S assembly is reversible and can be overcome by supplementation of aspartate or pyruvate. This metabolic regulation of 26S activity involves specific regulation of proteasome assembly factors via the mTORC1 pathway. Of note, reducing 26S activity by metformin confers increased resistance toward the proteasome inhibitor bortezomib, which is reversible upon pyruvate supplementation. Our study uncovers unexpected consequences of defective mitochondrial metabolism for proteasomal protein degradation in the cell, which has important pathophysiological and therapeutic implications. AU - Meul, T. AU - Berschneider, K. AU - Schmitt, S. AU - Mayr, C. AU - Mattner, L. AU - Schiller, H. B. AU - Yazgili, A.S. AU - Wang, X.* AU - Lukas, C. AU - Schlesser, C. AU - Prehn, C. AU - Adamski, J. AU - Graf, E. AU - Schwarzmayr, T. AU - Perocchi, F. AU - Kukat, A.* AU - Trifunovic, A.* AU - Kremer, L.S. AU - Prokisch, H. AU - Popper, B.* AU - von Toerne, C. AU - Hauck, S.M. AU - Zischka, H. AU - Meiners, S. C1 - 59978 C2 - 48974 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - Mitochondrial regulation of the 26S proteasome. JO - Cell Rep. VL - 32 IS - 8 PB - Cell Press PY - 2020 SN - 2211-1247 ER - TY - JOUR AB - The NIPBL/MAU2 heterodimer loads cohesin onto chromatin. Mutations in NIPBL account for most cases of the rare developmental disorder Cornelia de Lange syndrome (CdLS). Here we report a MAU2 variant causing CdLS, a deletion of seven amino acids that impairs the interaction between MAU2 and the NIPBL N terminus. Investigating this interaction, we discovered that MAU2 and the NIPBL N terminus are largely dispensable for normal cohesin and NIPBL function in cells with a NIPBL early truncating mutation. Despite a predicted fatal outcome of an out-of-frame single nucleotide duplication in NIPBL, engineered in two different cell lines, alternative translation initiation yields a form of NIPBL missing N-terminal residues. This form cannot interact with MAU2, but binds DNA and mediates cohesin loading. Altogether, our work reveals that cohesin loading can occur independently of functional NIPBL/MAU2 complexes and highlights a novel mechanism protective against out-of-frame mutations that is potentially relevant for other genetic conditions. AU - Parenti, I.* AU - Diab, F.* AU - Gil, S.R.* AU - Mulugeta, E.* AU - Casa, V.* AU - Berutti, R. AU - Brouwer, R.W.W.* AU - Dupé, V.* AU - Eckhold, J.* AU - Graf, E. AU - Puisac, B.* AU - Ramos, F.* AU - Schwarzmayr, T. AU - Gines, M.M.* AU - van Staveren, T.* AU - van IJcken, W.F.J.* AU - Strom, T.M. AU - Pié, J.* AU - Watrin, E.* AU - Kaiser, F.J.* AU - Wendt, K.S.* C1 - 59167 C2 - 48618 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa TI - MAU2 and NIPBL variants impair the heterodimerization of the cohesin loader subunits and cause Cornelia de Lange syndrome. JO - Cell Rep. VL - 31 IS - 7 PB - Cell Press PY - 2020 SN - 2211-1247 ER - TY - JOUR AB - The CARMA1/CARD11-BCL10-MALT1 (CBM) complex bridges T and B cell antigen receptor (TCR/BCR) ligation to MALT1 protease activation and canonical nuclear factor kappa B (NF-kappa B) signaling. Using unbiased mass spectrometry, we discover multiple serine phosphorylation sites in the MALT1 C terminus after T cell activation. Phospho-specific antibodies reveal that CBM-associated MALT1 is transiently hyper-phosphorylated upon TCR/CD28 co-stimulation. We identify a dual role for CK1 alpha as a kinase that is essential for CBM signalosome assembly as well as MALT1 phosphorylation. Although MALT1 phosphorylation is largely dispensable for protease activity, it fosters canonical NF-kappa B signaling in Jurkat and murine CD4 T cells. Moreover, constitutive MALT1 phosphorylation promotes survival of activated B cell-type diffuse large B cell lymphoma (ABC-DLBCL) cells addicted to chronic BCR signaling. Thus, MALT1 phosphorylation triggers optimal NF-kappa B activation in lymphocytes and survival of lymphoma cells. AU - Gehring, T. AU - Erdmann, T.* AU - Rahm, M. AU - Grass, C. AU - Flatley, A. AU - O´Neill, T.J. AU - Woods, S. AU - Meininger, I. AU - Karayel, O.* AU - Kutzner, K. AU - Grau, M.* AU - Shinohara, H.* AU - Lammens, K.* AU - Feederle, R. AU - Hauck, S.M. AU - Lenz, G.* AU - Krappmann, D. C1 - 57172 C2 - 47590 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 873-888.e10 TI - MALT1 phosphorylation controls activation of T lymphocytes and survival of ABC-DLBCL tumor cells. JO - Cell Rep. VL - 29 IS - 4 PB - Cell Press PY - 2019 SN - 2211-1247 ER - TY - JOUR AB - An insufficient adaptive beta-cell compensation is a hallmark of type 2 diabetes (T2D). Primary cilia function as versatile sensory antennae regulating various cellular processes, but their role on compensatory beta-cell replication has not been examined. Here, we identify a significant enrichment of downregulated, cilia-annotated genes in pancreatic islets of diabetes-prone NZO mice as compared with diabetes-resistant B6-ob/ob mice. Among 327 differentially expressed mouse cilia genes, 81 human orthologs are also affected in islets of diabetic donors. Islets of nondiabetic mice and humans show a substantial overlap of upregulated cilia genes that are linked to cell-cycle progression. The shRNA-mediated suppression of KIF3A, essential for ciliogenesis, impairs division of MINE beta cells as well as in dispersed primary mouse and human islet cells, as shown by decreased BrdU incorporation. These findings demonstrate the substantial role of cilia-gene regulation on islet function and T2D risk. AU - Kluth, O.* AU - Stadion, M.* AU - Gottmann, P.* AU - Aga, H.* AU - Jähnert, M.* AU - Scherneck, S.* AU - Vogel, H.* AU - Krus, U.* AU - Seelig, A. AU - Ling, C.* AU - Gerdes, J.M. AU - Schürmann, A.* C1 - 55636 C2 - 46462 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 3027-3036.e3 TI - Decreased expression of cilia genes in pancreatic islets as a risk factor for type 2 diabetes in mice and humans. JO - Cell Rep. VL - 26 IS - 11 PB - Cell Press PY - 2019 SN - 2211-1247 ER - TY - JOUR AB - Aerobic organisms need to maintain cellular redox homeostasis. Glutathione peroxidase-4 (Gpx4) has the unique ability to protect cells against lipid peroxidation. Here, we show that Gpx4 is absolutely required to prevent ferroptosis during development, maintenance, and responses of innate-like B cells, namely, the B1 and marginal zone (MZ) B cells. In contrast, Gpx4 is dispensable for the development, germinal center reactions, and antibody responses of follicular B2 cells. Mechanistically, we show increased lipid metabolism and sensitivity to lipid peroxidation and ferroptosis in B1 and MZ B cells compared to follicular B2 cells, consistent with the requirement of Gpx4 in innate-like B cells. This high sensitivity to ferroptosis of innate-like B cells may be used to therapeutically target Gpx4 in certain forms of B cell malignancies involving B1 cells. AU - Muri, J.* AU - Thut, H.* AU - Bornkamm, G.W. AU - Kopf, M.* C1 - 57467 C2 - 47811 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 2731-2744.e4 TI - B1 and marginal zone B cells but not follicular B2 cells require Gpx4 to prevent lipid peroxidation and ferroptosis. JO - Cell Rep. VL - 29 IS - 9 PB - Cell Press PY - 2019 SN - 2211-1247 ER - TY - JOUR AB - The Ebola virus glycoprotein (EBOV-GP) forms GP-containing microvesicles, so-called virosomes, which are secreted from GP-expressing cells. However, determinants of GP-virosome release and their functionality are poorly understood. We characterized GP-mediated virosome formation and delineated the role of the antiviral factor tetherin (BST2, CD317) in this process. Residues in the EBOV-GP receptor-binding domain (RBD) promote GP-virosome secretion, while tetherin suppresses GP-virosomes by interactions involving the GP-transmembrane domain. Tetherin from multiple species interfered with GP-virosome release, and tetherin from the natural fruit bat reservoir showed the highest inhibitory activity. Moreover, analyses of GP from various ebo-lavirus strains, including the EBOV responsible for the West African epidemic, revealed the most efficient GP-virosome formation by highly pathogenic ebolaviruses. Finally, EBOV-GP-virosomes were immunomodulatory and acted as decoys for EBOV-neutralizing antibodies. Our results indicate that GP-virosome formation might be a determinant of EBOV immune evasion and pathogenicity, which is suppressed by tetherin. AU - Nehls, J. AU - Businger, R.* AU - Hoffmann, M.* AU - Brinkmann, C.* AU - Fehrenbacher, B.* AU - Schaller, M.* AU - Maurer, B.* AU - Schönfeld, C.* AU - Kramer, D.* AU - Hailfinger, S.* AU - Pöhlmann, S.* AU - Schindler, M. C1 - 55486 C2 - 46356 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 1841-1853.e6 TI - Release of immunomodulatory Ebola virus glycoprotein-containingmicrovesicles is suppressed by tetherin in a species-specific manner. JO - Cell Rep. VL - 26 IS - 7 PB - Cell Press PY - 2019 SN - 2211-1247 ER - TY - JOUR AB - In traditional optical imaging, limited light penetration constrains high-resolution interrogation to tissue surfaces. Optoacoustic imaging combines the superb contrast of optical imaging with deep penetration of ultrasound, enabling a range of new applications. We used multispectral optoacoustic tomography (MSOT) for functional and structural neuroimaging in mice at resolution, depth, and specificity unattainable by other neuroimaging modalities. Based on multispectral readouts, we computed hemoglobin gradient and oxygen saturation changes related to processing of somatosensory signals in different structures along the entire subcortical-cortical axis. Using temporal correlation analysis and seed-based maps, we reveal the connectivity between cortical, thalamic, and sub-thalamic formations. With the same modality, high-resolution structural tomography of intact mouse brain was achieved based on endogenous contrasts, demonstrating near-perfect matches with anatomical features revealed by histology. These results extend the limits of noninvasive observations beyond the reach of standard high-resolution neuroimaging, verifying the suitability of MSOT for small-animal studies. AU - Olefir, I. AU - Ghazaryan, A. AU - Yang, H. AU - Malekzadeh Najafabadi, J. AU - Glasl, S. AU - Symvoulidis, P. AU - O'Leary, V.B.* AU - Sergiadis, G.* AU - Ntziachristos, V. AU - Ovsepian, S.V. C1 - 55605 C2 - 46429 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 2833-2846.e3 TI - Spatial and spectral mapping and decomposition of neural dynamics and organization of the mouse brain with multispectral optoacoustic tomography. JO - Cell Rep. VL - 26 IS - 10 PB - Cell Press PY - 2019 SN - 2211-1247 ER - TY - JOUR AB - Complement dysregulation is a feature of many retinal diseases, yet mechanistic understanding at the cellular level is limited. Given this knowledge gap about which retinal cells express complement, we performed single-cell RNA sequencing on similar to 92,000 mouse retinal cells and validated our results in five major purified retinal cell types. We found evidence for a distributed cell-type-specific complement expression across 11 cell types. Notably, Muller cells are the major contributor of complement activators c1s, c3, c4, and cfb. Retinal pigment epithelium (RPE) mainly expresses cfh and the terminal complement components, whereas cfi and cfp transcripts are most abundant in neurons. Aging enhances c1s, cfb, cfp, and cfi expression, while cfh expression decreases. Transient retinal ischemia increases complement expression in microglia, Muller cells, and RPE. In summary, we report a unique complement expression signature for murine retinal cell types suggesting a well-orchestrated regulation of local complement expression in the retinal microenvironment. AU - Pauly, D.* AU - Agarwal, D.* AU - Dana, N.* AU - Schäfer, N.* AU - Biber, J.* AU - Wunderlich, K.A.* AU - Jabri, Y.* AU - Straub, T.* AU - Zhang, N.R.* AU - Gautam, A.K.* AU - Weber, B.H.F.* AU - Hauck, S.M. AU - Kim, M.* AU - Curcio, C.A.* AU - Stambolian, D.* AU - Li, M.* AU - Grosche, A.* C1 - 57468 C2 - 47812 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 2835-2848.e4 TI - Cell type-specific complement expression in the healthy and diseased retina. JO - Cell Rep. VL - 29 IS - 9 PB - Cell Press PY - 2019 SN - 2211-1247 ER - TY - JOUR AB - Transdifferentiation of fibroblasts into induced neuronal cells (iNs) by the neuron-specific transcription factors Brn2, Myt1l, and Ascl1 is a paradigmatic example of inter-lineage conversion across epigenetically distant cells. Despite tremendous progress regarding the transcriptional hierarchy underlying transdifferentiation, the enablers of the concomitant epigenome resetting remain to be elucidated. Here, we investigated the role of KMT2A and KMT2B, two histone H3 lysine 4 methylases with cardinal roles in development, through individual and combined inactivation. We found that Kmt2b, whose human homolog's mutations cause dystonia, is selectively required for iN conversion through suppression of the alternative myocyte program and induction of neuronal maturation genes. The identification of KMT2B-vulnerable targets allowed us, in turn, to expose, in a cohort of 225 patients, 45 unique variants in 39 KMT2B targets, which represent promising candidates to dissect the molecular bases of dystonia. AU - Barbagiovanni, G.* AU - Germain, P.L.* AU - Zech, M. AU - Atashpaz, S.* AU - Lo Riso, P.* AU - D'Antonio-Chronowska, A.* AU - Tenderini, E.* AU - Caiazzo, M.* AU - Boesch, S.* AU - Jech, R.* AU - Haslinger, B.* AU - Broccoli, V.* AU - Stewart, A.F.* AU - Winkelmann, J. AU - Testa, G.* C1 - 54592 C2 - 45698 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 988-1001 TI - KMT2B is selectively required for neuronal transdifferentiation and its loss exposes dystonia candidate genes. JO - Cell Rep. VL - 25 IS - 4 PB - Cell Press PY - 2018 SN - 2211-1247 ER - TY - JOUR AB - Adult murine neural stem cells (NSCs) generate neurons in drastically declining numbers with age. How cellular dynamics sustain neurogenesis and how alterations with age may result in this decline are unresolved issues. We therefore clonally traced NSC lineages using confetti reporters in young and middle-aged adult mice. To understand the underlying mechanisms, we derived mathematical models that explain observed clonal cell type abundances. The best models consistently show self-renewal of transit-amplifying progenitors and rapid neuroblast cell cycle exit. In middle-aged mice, we identified an increased probability of asymmetric stem cell divisions at the expense of symmetric differentiation, accompanied by an extended persistence of quiescence between activation phases. Our model explains existing longitudinal population data and identifies particular cellular properties underlying adult NSC homeostasis and the aging of this stem cell compartment. AU - Bast, L. AU - Calzolari, F. AU - Strasser, M. AU - Hasenauer, J. AU - Theis, F.J. AU - Ninkovic, J. AU - Marr, C. C1 - 54983 C2 - 46045 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 3231-3240.e8 TI - Increasing neural stem cell division asymmetry and quiescence are predicted to contribute to the age-related decline in neurogenesis. JO - Cell Rep. VL - 25 IS - 12 PB - Cell Press PY - 2018 SN - 2211-1247 ER - TY - JOUR AB - Protein arginine methyltransferase 6 (PRMT6) catalyzes asymmetric dimethylation of histone H3 at arginine 2 (H3R2me2a). This mark has been reported to associate with silent genes. Here, we use a cell model of neural differentiation, which upon PRMT6 knockout exhibits proliferation and differentiation defects. Strikingly, we detect PRMT6-dependent H3R2me2a at active genes, both at promoter and enhancer sites. Loss of H3R2me2a from promoter sites leads to enhanced KMT2A binding and H3K4me3 deposition together with increased target gene transcription, supporting a repressive nature of H3R2me2a. At enhancers, H3R2me2a peaks co-localize with the active enhancer marks H3K4me1 and H3K27ac. Here, loss of H3R2me2a results in reduced KMT2D binding and H3K4me1/H3K27ac deposition together with decreased transcription of associated genes, indicating that H3R2me2a also exerts activation functions. Our work suggests that PRMT6 via H3R2me2a interferes with the deposition of adjacent histone marks and modulates the activity of important differentiation-associated genes by opposing transcriptional effects. AU - Bouchard, C.* AU - Sahu, P.* AU - Meixner, M.* AU - Nötzold, R.R.* AU - Rust, M.B.* AU - Kremmer, E. AU - Feederle, R. AU - Hart-Smith, G.* AU - Finkernagel, F.* AU - Bartkuhn, M.* AU - Savai Pullamsetti, S.* AU - Nist, A.* AU - Stiewe, T.* AU - Philipsen, S.* AU - Bauer, U.M.* C1 - 54318 C2 - 45489 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 3339-3352 TI - Genomic location of PRMT6-dependent H3R2 methylation is linked to the transcriptional outcome of associated genes. JO - Cell Rep. VL - 24 IS - 12 PB - Cell Press PY - 2018 SN - 2211-1247 ER - TY - JOUR AB - Skin affections after sulfur mustard (SM) exposure include erythema, blister formation and severe inflammation. An antidote or specific therapy does not exist. Anti-inflammatory compounds as well as substances counteracting SM-induced cell death are under investigation. In this study, we investigated the benzylisoquinoline alkaloide berberine (BER), a metabolite in plants like berberis vulgaris, which is used as herbal pharmaceutical in Asian countries, against SM toxicity using a well-established in vitro approach. Keratinocyte (HaCaT) mono-cultures (MoC) or HaCaT/THP-1 co-cultures (CoC) were challenged with 100, 200 or 300 mM SM for 1 h. Post-exposure, both MoC and CoC were treated with 10, 30 or 50 mu M BER for 24 h. At that time, supernatants were collected and analyzed both for interleukine (IL) 6 and 8 levels and for content of adenylate-kinase (AK) as surrogate marker for cell necrosis. Cells were lysed and nucleosome formation as marker for late apoptosis was assessed. In parallel, AK in cells was determined for normalization purposes. BER treatment did not influence necrosis, but significantly decreased apoptosis. Anti-inflammatory effects were moderate, but also significant, primarily in CoC. Overall, BER has protective effects against SM toxicity in vitro. Whether this holds true should be evaluated in future in vivo studies. AU - Cheng, Y. AU - Jiang, L. AU - Keipert, S. AU - Zhang, S. AU - Hauser, A.* AU - Graf, E. AU - Strom, T.M. AU - Tschöp, M.H. AU - Jastroch, M. AU - Perocchi, F. C1 - 53613 C2 - 44926 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - 3112-3125 TI - Prediction of adipose browning capacity by systematic integration of transcriptional profiles. JO - Cell Rep. VL - 23 IS - 10 PB - Elsevier Ireland Ltd PY - 2018 SN - 2211-1247 ER - TY - JOUR AB - Zebrafish have a high capacity to replace lost neurons after brain injury. New neurons involved in repair are generated by a specific set of glial cells, known as ependymoglial cells. We analyze changes in the transcriptome of ependymoglial cells and their progeny after injury to infer the molecular pathways governing restorative neurogenesis. We identify the aryl hydrocarbon receptor (AhR) as a regulator of ependymoglia differentiation toward post-mitotic neurons. In vivo imaging shows that high AhR signaling promotes the direct conversionof a specific subset of ependymoglia into post-mitotic neurons, while low AhR signaling promotes ependymoglial proliferation. Interestingly, we observe the inactivation of AhR signaling shortly after injury followed by a return to the basal levels 7 days post injury. Interference with timely AhR regulation after injury leads to aberrant restorative neurogenesis. Taken together, we identify AhR signaling as a crucial regulator of restorative neurogenesis timing in the zebrafish brain. AU - di Giaimo, R. AU - Durovic, T. AU - Barquin, P.* AU - Kociaj, A. AU - Lepko, T. AU - Aschenbroich, S. AU - Breunig, C. AU - Irmler, M. AU - Cernilogar, F.M.* AU - Schotta, G.* AU - Barbosa, J.S. AU - Trümbach, D. AU - Baumgart, E.V. AU - Neuner, A.M. AU - Beckers, J. AU - Wurst, W. AU - Stricker, S.H. AU - Ninkovic, J. C1 - 54915 C2 - 45964 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 3241-3251.e5 TI - The aryl hydrocarbon receptor pathway defines the time frame for restorative neurogenesis. JO - Cell Rep. VL - 25 IS - 12 PB - Cell Press PY - 2018 SN - 2211-1247 ER - TY - JOUR AB - Neurogenesis continues in the ventricular-subventricular zone (V-SVZ) of the adult forebrain from quiescent neural stem cells (NSCs). V-SVZ NSCs are a reservoir for new olfactory bulb (OB) neurons that migrate through the rostral migratory stream (RMS). To generate neurons, V-SVZ NSCs need to activate and enter the cell cycle. The mechanisms underlying NSC transition from quiescence to activity are poorly understood. We show that Notch2, but not Notch1, signaling conveys quiescence to V-SVZ NSCs by repressing cell-cycle-related genes and neurogenesis. Loss of Notch2 activates quiescent NSCs, which proliferate and generate new neurons of the OB lineage. Notch2 deficiency results in accelerated V-SVZ NSC exhaustion and an aging-like phenotype. Simultaneous loss of Notch1 and Notch2 resembled the total loss of Rbpj-mediated canonical Notch signaling; thus, Notch2 functions are not compensated in NSCs, and Notch2 is indispensable for the maintenance of NSC quiescence in the adult V-SVZ. Using a combinatorial knockout approach, Engler et al. systematically analyze Notch signaling mutants. Their study demonstrates the role of Notch2 in the maintenance of quiescent NSCs in the adult murine brain. AU - Engler, A.* AU - Rolando, C.* AU - Giachino, C.* AU - Saotome, I.* AU - Erni, A.* AU - Brien, C.* AU - Zhang, R.* AU - Zimber-Strobl, U. AU - Radtke, F.* AU - Artavanis-Tsakonas, S.* AU - Louvi, A.* AU - Taylor, V.* C1 - 52860 C2 - 44385 CY - Cambridge SP - 992-1002 TI - Notch2 signaling maintains NSC quiescence in the murine ventricular-subventricular zone. JO - Cell Rep. VL - 22 IS - 4 PB - Cell Press PY - 2018 SN - 2211-1247 ER - TY - JOUR AB - Diet, genetics, and the gut microbiome are determinants of metabolic status, in part through production of metabolites by the gut microbiota. To understand the mechanisms linking these factors, we performed LC-MS-based metabolomic analysis of cecal contents and plasma from C57BL/6J, 129S1/SvImJ, and 129S6/SvEvTac mice on chow or a high-fat diet (HFD) and HFD-treated with vancomycin or metronidazole. Prediction of the functional metagenome of gut bacteria by PICRUSt analysis of 16S sequences revealed dramatic differences in microbial metabolism. Cecal and plasma metabolites showed multifold differences reflecting the combined and integrated effects of diet, antibiotics, host background, and the gut microbiome. Eighteen plasma metabolites correlated positively or negatively with host insulin resistance across strains and diets. Over 1,000 still-unidentified metabolite peaks were also highly regulated by diet, antibiotics, and genetic background. Thus, diet, host genetics, and the gut microbiota interact to create distinct responses in plasma metabolites, which can contribute to regulation of metabolism and insulin resistance. AU - Fujisaka, S.* AU - Avila-Pacheco, J.* AU - Soto, M.* AU - Kostic, A.* AU - Dreyfuss, J.M.* AU - Pan, H.* AU - Ussar, S. AU - Altindis, E.* AU - Li, N.* AU - Bry, L.* AU - Clish, C.B.* AU - Kahn, C.R.* C1 - 53256 C2 - 44643 CY - Cambridge SP - 3072-3086 TI - Diet, genetics, and the gut microbiome drive dynamic changes in plasma metabolites. JO - Cell Rep. VL - 22 IS - 11 PB - Cell Press PY - 2018 SN - 2211-1247 ER - TY - JOUR AB - The mammalian neocortex has undergone remarkable changes through evolution. A consequence of such rapid evolutionary events could be a trade-off that has rendered the brain susceptible to certain neurodevelopmental and neuropsychiatric conditions. We analyzed the exomes of 65 patients with the structural brain malformation periventricular nodular heterotopia (PH). De novo coding variants were observed in excess in genes defining a transcriptomic signature of basal radial glia, a cell type linked to brain evolution. In addition, we located two variants in human isoforms of two genes that have no ortholog in mice. Modulating the levels of one of these isoforms for the gene PLEKHG6 demonstrated its role in regulating neuroprogenitor differentiation and neuronal migration via RhoA, with phenotypic recapitulation of PH in human cerebral organoids. This suggests that this PLEKHG6 isoform is an example of a primate-specific genomic element supporting brain development. AU - O'Neill, A.C. AU - Kyrousi, C.* AU - Klaus, J.* AU - Leventer, R.J.* AU - Kirk, E.P.* AU - Fry, A.* AU - Pilz, D.T.* AU - Morgan, T.* AU - Jenkins, Z.A.* AU - Drukker, M. AU - Berkovic, S.F.* AU - Scheffer, I.E.* AU - Guerrini, R.* AU - Markie, D.M.* AU - Götz, M. AU - Cappello, S.* AU - Robertson, S.P.* C1 - 54864 C2 - 45889 SP - 2729-2741.e6 TI - A primate-specific isoform of PLEKHG6 regulates neurogenesis and neuronal migration. JO - Cell Rep. VL - 25 IS - 10 PY - 2018 SN - 2211-1247 ER - TY - JOUR AB - Foxp3(+) regulatory T cells (Treg) are essential modulators of immune responses, but the molecular mechanisms underlying their function are not fully understood. Here we show that the transcription factor Blimp-1 is a crucial regulator of the Foxp3(+)ROR gamma t(+) Treg subset. The intrinsic expression of Blimp-1 in these cells is required to prevent production of Th17-associated cytokines. Direct binding of Blimp-1 to the II17 locus in Treg is associated with inhibitory histone modifications but unaltered binding of ROR gamma t. In the absence of Blimp-1, the II17 locus is activated, with increased occupancy of the co-activator p300 and abundant binding of the transcriptional regulator IRF4, which is required, along with ROR gamma t, for IL-17 expression in the absence of Blimp-1. We also show that despite their sustained expression of Foxp3, Blimp-1(-/-) ROR gamma t(+)IL-17-producing Treg lose suppressor function and can promote intestinal inflammation, indicating that repression of Th17-associated cytokines by Blimp-1 is a crucial requirement for ROR gamma t(+) Treg function. AU - Ogawa, C.* AU - Bankoti, R.* AU - Nguyen, T.* AU - Hassanzadeh-Kiabi, N.* AU - Nadeau, S.* AU - Porritt, R.A.* AU - Couse, M.* AU - Fan, X.* AU - Dhall, D.* AU - Eberl, G.* AU - Ohnmacht, C. AU - Martins, G.A.* C1 - 54421 C2 - 45541 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 19-28.e5 TI - Blimp-1 functions as a molecular switch to prevent inflammatory activity in Foxp3+ ROR gamma t+ regulatory T cells. JO - Cell Rep. VL - 25 IS - 1 PB - Cell Press PY - 2018 SN - 2211-1247 ER - TY - JOUR AB - Centrosomes are the major microtubule-organizing centers, consisting of centrioles surrounded by a pericentriolar material (PCM). Centrosomal PCM is spatiotemporally regulated to be minimal during interphase and expands as cells enter mitosis. It is unclear how PCM expansion is initiated at the onset of mitosis. Here, we identify that, in Drosophila, Plk1/Polo kinase phosphorylates the conserved centrosomal protein Sas-4 in vitro. This phosphorylation appears to occur at the onset of mitosis, enabling Sas-4's localization to expand outward from meiotic and mitotic centrosomes. The Plk1/Polo kinase site of Sas-4 is then required for an efficient recruitment of Cnn and gamma-tubulin, bona fide PCM proteins that are essential for PCM expansion and centrosome maturation. Point mutations at Plk1/Polo sites of Sas-4 affect neither centrosome structure nor centriole duplication but specifically reduce the affinity to bind Cnn and gamma-tubulin. These observations identify Plk1/Polo kinase regulation of Sas-4 as essential for efficient PCM expansion. AU - Ramani, A.* AU - Mariappan, A.* AU - Gottardo, M.* AU - Mandad, S.* AU - Urlaub, H.* AU - Avidor-Reiss, T.* AU - Riparbelli, M.* AU - Callaini, G.* AU - Debec, A.* AU - Feederle, R. AU - Gopalakrishnan, J.* C1 - 55039 C2 - 46061 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 3618-3630.e6 TI - Plk1/Polo phosphorylates Sas-4 at the onset of mitosis for an efficient recruitment of pericentriolar material to centrosomes. JO - Cell Rep. VL - 25 IS - 13 PB - Cell Press PY - 2018 SN - 2211-1247 ER - TY - JOUR AB - Adrenal insufficiency is managed by hormone replacement therapy, which is far from optimal; the ability to generate functional steroidogenic cells would offer a unique opportunity for a curative approach to restoring the complex feedback regulation of the hypothalamic-pituitary-adrenal axis. Here, we generated human induced steroidogenic cells (hiSCs) from fibroblasts, blood-, and urine-derived cells through forced expression of steroidogenic factor-1 and activation of the PKA and LHRH pathways. hiSCs had ultrastructural features resembling steroid-secreting cells, expressed steroidogenic enzymes, and secreted steroid hormones in response to stimuli. hiSCs were viable when transplanted into the mouse kidney capsule and intra-adrenal. Importantly, the hypocortisolism of hiSCs derived from patients with adrenal insufficiency due to congenital adrenal hyperplasia was rescued by expressing the wild-type version of the defective disease-causing enzymes. Our study provides an effective tool with many potential applications for studying adrenal pathobiology in a personalized manner and opens venues for the development of precision therapies. AU - Ruiz-Babot, G.* AU - Balyura, M.* AU - Hadjidemetriou, I.* AU - Ajodha, S.J.* AU - Taylor, D.R.* AU - Ghataore, L.* AU - Taylor, N.F.* AU - Schubert, U.* AU - Ziegler, C.G.* AU - Storr, H.L.* AU - Druce, M.R.* AU - Gevers, E.F.* AU - Drake, W.M.* AU - Srirangalingam, U.* AU - Conway, G.S.* AU - King, P.J.* AU - Metherell, L.A.* AU - Bornstein, S.R. AU - Guasti, L.* C1 - 52861 C2 - 44384 CY - Cambridge SP - 1236-1249 TI - Modeling congenital adrenal hyperplasia and testing interventions for adrenal insufficiency using donor-specific reprogrammed cells. JO - Cell Rep. VL - 22 IS - 5 PB - Cell Press PY - 2018 SN - 2211-1247 ER - TY - JOUR AB - The mitochondrial calcium uniporter is a highly selective ion channel composed of species-and tissue-specific subunits. However, the functional role of each component still remains unclear. Here, we establish a synthetic biology approach to dissect the interdependence between the pore-forming subunit MCU and the calcium-sensing regulator MICU1. Correlated evolutionary patterns across 247 eukaryotes indicate that their co-occurrence may have conferred a positive fitness advantage. We find that, while the heterologous reconstitution of MCU and EMRE in vivo in yeast enhances manganese stress, this is prevented by co-expression of MICU1. Accordingly, MICU1 deletion sensitizes human cells to manganese-dependent cell death by disinhibiting MCU-mediated manganese uptake. As a result, manganese overload increases oxidative stress, which can be effectively prevented by NAC treatment. Our study identifies a critical contribution of MICU1 to the uniporter selectivity, with important implications for patients with MICU1 deficiency, as well as neurological disorders arising upon chronic manganese exposure. AU - Wettmarshausen, J. AU - Goh, V. AU - Huang, K.T.* AU - Arduino, D.M. AU - Tripathi, U.* AU - Leimpek, A. AU - Cheng, Y. AU - Pittis, A.A.* AU - Gabaldón, T.* AU - Mokranjac, D.* AU - Hajnóczky, G.* AU - Perocchi, F. C1 - 54661 C2 - 45756 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 1425-1435 TI - MICU1 confers protection from MCU-dependent manganese toxicity. JO - Cell Rep. VL - 25 IS - 6 PB - Cell Press PY - 2018 SN - 2211-1247 ER - TY - JOUR AB - Clathrin/adaptor protein-1-coated carriers connect the secretory and the endocytic pathways. Carrier biogenesis relies on distinct protein networks changing membrane shape at the trans-Golgi network, each regulating coat assembly, F-actin-based mechanical forces, or the biophysical properties of lipid bilayers. How these different hubs are spatiotemporally coordinated remains largely unknown. Using in vitro reconstitution systems, quantitative proteomics, and lipidomics, as well as in vivo cell-based assays, we characterize the protein networks controlling membrane lipid composition, membrane shape, and carrier scission. These include PIP5K1A and phospholipase C-beta 3 controlling the conversion of PI[4]P into diacylglycerol. PIP5K1A binding to RAC1 provides a link to F-actin-based mechanical forces needed to tubulate membranes. Tubular membranes then recruit the BAR-domain-containing arfaptin-1/2 guiding carrier scission. These findings provide a framework for synchronizing the chemical/biophysical properties of lipid bilayers, F-actin-based mechanical forces, and the activity of proteins sensing membrane shape during clathrin/adaptor protein-1-coated carrier biogenesis. AU - Anitei, M.* AU - Stange, C.* AU - Czupalla, C.* AU - Niehage, C.* AU - Schuhmann, K.* AU - Sala, P. AU - Czogalla, A. AU - Pursche, T.* AU - Coskun, Ü. AU - Shevchenko, A.* AU - Hoflack, B.* C1 - 51780 C2 - 43520 CY - Cambridge SP - 2087-2099 TI - Spatiotemporal control of lipid conversion, actin-based mechanical forces, and curvature sensors during clathrin/AP-1-coated vesicle biogenesis. JO - Cell Rep. VL - 20 IS - 9 PB - Cell Press PY - 2017 SN - 2211-1247 ER - TY - JOUR AB - Regular endurance training improves muscle oxidative capacity and reduces the risk of age-related disorders. Understanding the molecular networks underlying this phenomenon is crucial. Here, by exploiting the power of computational modeling, we show that endurance training induces profound changes in gene regulatory networks linking signaling and selective control of translation to energy metabolism and tissue remodeling. We discovered that knockdown of the mTOR-independent factor Eif6, which we predicted to be a key regulator of this process, affects mitochondrial respiration efficiency, ROS production, and exercise performance. Our work demonstrates the validity of a data-driven approach to understanding muscle homeostasis. AU - Clarke, K.* AU - Ricciardi, S.* AU - Pearson, T.* AU - Bharudin, I.* AU - Davidsen, P.K.* AU - Bonomo, M.* AU - Brina, D.* AU - Scagliola, A.* AU - Simpson, D.M.* AU - Beynon, R.J.* AU - Khanim, F.* AU - Ankers, J.* AU - Sarzynski, M.A.* AU - Ghosh, S.* AU - Pisconti, A.* AU - Rozman, J. AU - Hrabě de Angelis, M. AU - Bunce, C.* AU - Stewart, C.* AU - Egginton, S.* AU - Caddick, M.* AU - Jackson, M.A.* AU - Bouchard, C.* AU - Biffo, S.* AU - Falciani, F.* C1 - 52294 C2 - 43898 CY - Cambridge SP - 1507-1520 TI - The role of Eif6 in skeletal muscle homeostasis revealed by endurance training co-expression networks. JO - Cell Rep. VL - 21 IS - 6 PB - Cell Press PY - 2017 SN - 2211-1247 ER - TY - JOUR AB - Activation of immune cells results in rapid functional changes, but how such fast changes are accomplished remains enigmatic. By combining time courses of 4sU-seq, RNA-seq, ribosome profiling (RP), and RNA polymerase II (RNA Pol II) ChIP-seq during T cell activation, we illustrate genome-wide temporal dynamics for ∼10,000 genes. This approach reveals not only immediate-early and posttranscriptionally regulated genes but also coupled changes in transcription and translation for >90% of genes. Recruitment, rather than release of paused RNA Pol II, primarily mediates transcriptional changes. This coincides with a genome-wide temporary slowdown in cotranscriptional splicing, even for polyadenylated mRNAs that are localized at the chromatin. Subsequent splicing optimization correlates with increasing Ser-2 phosphorylation of the RNA Pol II carboxy-terminal domain (CTD) and activation of the positive transcription elongation factor (pTEFb). Thus, rapid de novo recruitment of RNA Pol II dictates the course of events during T cell activation, particularly transcription, splicing, and consequently translation. AU - Davari, K. AU - Lichti, J. AU - Gallus, C. AU - Greulich, F. AU - Uhlenhaut, N.H. AU - Heinig, M. AU - Friedel, C.C.* AU - Glasmacher, E. C1 - 50963 C2 - 43036 SP - 643-654 TI - Rapid genome-wide recruitment of RNA polymerase II drives transcription, splicing, and translation events during T cell responses. JO - Cell Rep. VL - 19 IS - 3 PY - 2017 SN - 2211-1247 ER - TY - JOUR AB - Consumption of a hypercaloric diet upregulates microglial innate immune reactivity along with a higher expression of lipoprotein lipase (Lpl) within the reactive microglia in the mouse brain. Here, we show that knockdown of the Lpl gene specifically in microglia resulted in deficient microglial uptake of lipid, mitochondrial fuel utilization shifting to glutamine, and significantly decreased immune reactivity. Mice with knockdown of the Lpl gene in microglia gained more body weight than control mice on a high-carbohydrate high-fat (HCHF) diet. In these mice, microglial reactivity was significantly decreased in the mediobasal hypothalamus, accompanied by downregulation of phagocytic capacity and increased mitochondrial dysmorphologies. Furthermore, HCHF-diet-induced POMC neuronal loss was accelerated. These results show that LPL-governed microglial immunometabolism is essential to maintain microglial function upon exposure to an HCHF diet. In a hypercaloric environment, lack of such an adaptive immunometabolic response has detrimental effects on CNS regulation of energy metabolism. AU - Gao, Y.* AU - Vidal-Itriago, A.* AU - Kalsbeek, M.J.* AU - Layritz, C. AU - García-Cáceres, C. AU - Tom, R.Z. AU - Eichmann, T.O.* AU - Vaz, F.M.* AU - Houtkooper, R.H.* AU - van der Wel, N.* AU - Verhoeven, A.J.* AU - Yan, J.* AU - Kalsbeek, A.* AU - Eckel, R.H.* AU - Hofmann, S.M. AU - Yi, C.X.* C1 - 52003 C2 - 43656 CY - Cambridge SP - 3034-3042 TI - Lipoprotein lipase maintains microglial innate immunity in obesity. JO - Cell Rep. VL - 20 IS - 13 PB - Cell Press PY - 2017 SN - 2211-1247 ER - TY - JOUR AB - Increased pro-inflammatory signaling is a hallmark of metabolic dysfunction in obesity and diabetes. Although both inflammatory and energy substrate handling processes represent critical layers of metabolic control, their molecular integration sites remain largely unknown. Here, we identify the heterodimerization interface between the α and β subunits of transcription factor GA-binding protein (GAbp) as a negative target of tumor necrosis factor alpha (TNF-α) signaling. TNF-α prevented GAbpα and β complex formation via reactive oxygen species (ROS), leading to the non-energy-dependent transcriptional inactivation of AMP-activated kinase (AMPK) β1, which was identified as a direct hepatic GAbp target. Impairment of AMPKβ1, in turn, elevated downstream cellular cholesterol biosynthesis, and hepatocyte-specific ablation of GAbpα induced systemic hypercholesterolemia and early macro-vascular lesion formation in mice. As GAbpα and AMPKβ1 levels were also found to correlate in obese human patients, the ROS-GAbp-AMPK pathway may represent a key component of a hepato-vascular axis in diabetic long-term complications. AU - Niopek, K. AU - Üstünel, B.E. AU - Seitz, S. AU - Sakurai, M. AU - Zota, A. AU - Mattijssen, F. AU - Wang, X.* AU - Sijmonsma, T.* AU - Feuchter, Y.* AU - Gail, A.M.* AU - Leuchs, B.* AU - Niopek, D.* AU - Staufer, O. AU - Brune, M. AU - Sticht, C.* AU - Gretz, N.* AU - Müller-Decker, K.* AU - Hammes, H.P.* AU - Nawroth, P.P. AU - Fleming, T.* AU - Conkright, M.D.* AU - Blüher, M.* AU - Zeigerer, A. AU - Herzig, S. AU - Berriel Diaz, M. C1 - 51698 C2 - 43339 CY - Cambridge SP - 1422-1434 TI - A hepatic GAbp-AMPK axis links inflammatory signaling to systemic vascular damage. JO - Cell Rep. VL - 20 IS - 6 PB - Cell Press PY - 2017 SN - 2211-1247 ER - TY - JOUR AB - Many RNA-binding proteins (RBPs) regulate both alternative exons and poly(A) site selection. To understand their regulatory principles, we developed expressRNA, a web platform encompassing computational tools for integration of iCLIP and RNA motif analyses with RNA-seq and 3' mRNA sequencing. This reveals at nucleotide resolution the "RNA maps" describing how the RNA binding positions of RBPs relate to their regulatory functions. We use this approach to examine how TDP-43, an RBP involved in several neurodegenerative diseases, binds around its regulated poly(A) sites. Binding close to the poly(A) site generally represses, whereas binding further downstream enhances use of the site, which is similar to TDP-43 binding around regulated exons. Our RNAmotifs2 software also identifies sequence motifs that cluster together with the binding motifs of TDP-43. We conclude that TDP-43 directly regulates diverse types of pre-mRNA processing according to common position-dependent principles. AU - Rot, G.* AU - Wang, Z.* AU - Huppertz, I.* AU - Modic, M. AU - Lenče, T.* AU - Hallegger, M.* AU - Haberman, N.* AU - Curk, T.* AU - von Mering, C.* AU - Ule, J.* C1 - 51070 C2 - 43057 CY - Cambridge SP - 1056-1067 TI - High-resolution RNA maps suggest common principles of splicing and polyadenylation regulation by TDP-43. JO - Cell Rep. VL - 19 IS - 5 PB - Cell Press PY - 2017 SN - 2211-1247 ER - TY - JOUR AB - Lipoprotein synthesis is controlled by estrogens, but the exact mechanisms underpinning this regulation and the role of the hepatic estrogen receptor α (ERα) in cholesterol physiology are unclear. Utilizing a mouse model involving selective ablation of ERα in the liver, we demonstrate that hepatic ERα couples lipid metabolism to the reproductive cycle. We show that this receptor regulates the synthesis of cholesterol transport proteins, enzymes for lipoprotein remodeling, and receptors for cholesterol uptake. Additionally, ERα is indispensable during proestrus for the generation of high-density lipoproteins efficient in eliciting cholesterol efflux from macrophages. We propose that a specific interaction with liver X receptor α (LXRα) mediates the broad effects of ERα on the hepatic lipid metabolism. AU - Della Torre, S.* AU - Mitro, N.* AU - Fontana, R.* AU - Gomaraschi, M.* AU - Favari, E.* AU - Recordati, C.* AU - Lolli, F.* AU - Quagliarini, F. AU - Meda, C.* AU - Ohlsson, C.* AU - Crestani, M.* AU - Uhlenhaut, N.H. AU - Calabresi, L.* AU - Maggi, A.* C1 - 48262 C2 - 41006 CY - Cambridge SP - 360-371 TI - An essential role for liver ERα in coupling hepatic metabolism to the reproductive cycle. JO - Cell Rep. VL - 15 IS - 2 PB - Cell Press PY - 2016 SN - 2211-1247 ER - TY - JOUR AB - Although epithelial NF-κB signaling is important for lung carcinogenesis, NF-κB inhibitors are ineffective for cancer treatment. To explain this paradox, we studied mice with genetic deletion of IKKβ in myeloid cells and found enhanced tumorigenesis in Kras(G12D) and urethane models of lung cancer. Myeloid-specific inhibition of NF-κB augmented pro-IL-1β processing by cathepsin G in neutrophils, leading to increased IL-1β and enhanced epithelial cell proliferation. Combined treatment with bortezomib, a proteasome inhibitor that blocks NF-κB activation, and IL-1 receptor antagonist reduced tumor formation and growth in vivo. In lung cancer patients, plasma IL-1β levels correlated with poor prognosis, and IL-1β increased following bortezomib treatment. Together, our studies elucidate an important role for neutrophils and IL-1β in lung carcinogenesis and resistance to NF-κB inhibitors. AU - McLoed, A.G.* AU - Sherrill, T.P.* AU - Cheng, D.S.* AU - Han, W.* AU - Saxon, J.A.* AU - Gleaves, L.A.* AU - Wu, P.* AU - Polosukhin, V.V.* AU - Karin, M.* AU - Yull, F.E.* AU - Stathopoulos, G.T. AU - Georgoulias, V.* AU - Zaynagetdinov, R.* AU - Blackwell, T.S.* C1 - 48843 C2 - 41448 CY - Cambridge SP - 120-132 TI - Neutrophil-derived IL-1β impairs the efficacy of NF-κB inhibitors against lung cancer. JO - Cell Rep. VL - 16 IS - 1 PB - Cell Press PY - 2016 SN - 2211-1247 ER - TY - JOUR AB - 5-methylcytosine (5mC) is converted to 5-hydroxymethylcytosine (5hmC) by the TET family of enzymes as part of a recently discovered active DNA de-methylation pathway. 5hmC plays important roles in regulation of gene expression and differentiation and has been implicated in T cell malignancies and autoimmunity. Here, we report early and widespread 5mC/5hmC remodeling during human CD4(+) T cell differentiation ex vivo at genes and cell-specific enhancers with known T cell function. We observe similar DNA de-methylation in CD4(+) memory T cells in vivo, indicating that early remodeling events persist long term in differentiated cells. Underscoring their important function, 5hmC loci were highly enriched for genetic variants associated with T cell diseases and T-cell-specific chromosomal interactions. Extensive functional validation of 22 risk variants revealed potentially pathogenic mechanisms in diabetes and multiple sclerosis. Our results support 5hmC-mediated DNA de-methylation as a key component of CD4(+) T cell biology in humans, with important implications for gene regulation and lineage commitment. AU - Nestor, C.E.* AU - Lentini, A.* AU - Hägg Nilsson, C.* AU - Gawel, D.R.* AU - Gustafsson, M.* AU - Mattson, L.* AU - Wang, H.* AU - Rundquist, O.* AU - Meehan, R.R.* AU - Klocke, B.* AU - Seifert, M.* AU - Hauck, S.M. AU - Laumen, H. AU - Zhang, H.* AU - Benson, M.* C1 - 48903 C2 - 41474 CY - Cambridge SP - 559-570 TI - 5-hydroxymethylcytosine remodeling precedes lineage specification during differentiation of human CD4+ T cells. JO - Cell Rep. VL - 16 IS - 2 PB - Cell Press PY - 2016 SN - 2211-1247 ER - TY - JOUR AB - Cells in our body can induce hundreds of antiviral genes following virus sensing, many of which remain largely uncharacterized. CEACAM1 has been previously shown to be induced by various innate systems; however, the reason for such tight integration to innate sensing systems was not apparent. Here, we show that CEACAM1 is induced following detection of HCMV and influenza viruses by their respective DNA and RNA innate sensors, IFI16 and RIG-I. This induction is mediated by IRF3, which bound to an ISRE element present in the human, but not mouse, CEACAM1 promoter. Furthermore, we demonstrate that, upon induction, CEACAM1 suppresses both HCMV and influenza viruses in an SHP2-dependent process and achieves this broad antiviral efficacy by suppressing mTOR-mediated protein biosynthesis. Finally, we show that CEACAM1 also inhibits viral spread in ex vivo human decidua organ culture. AU - Vitenshtein, A.* AU - Weisblum, Y.* AU - Hauka, S.* AU - Halenius, A.* AU - Oiknine-Djian, E.* AU - Tsukerman, P.* AU - Bauman, Y.* AU - Bar-On, Y.* AU - Stern-Ginossar, N.* AU - Enk, J.* AU - Ortenberg, R.* AU - Tai, J.* AU - Markel, G.* AU - Blumberg, R.S.* AU - Hengel, H.* AU - Jonjic, S.* AU - Wolf, D.G.* AU - Adler, H. AU - Kammerer, R.* AU - Mandelboim, O.* C1 - 48761 C2 - 41311 CY - Cambridge SP - 2331-2339 TI - CEACAM1-mediated inhibition of virus production. JO - Cell Rep. VL - 15 IS - 11 PB - Cell Press PY - 2016 SN - 2211-1247 ER - TY - JOUR AB - Targeted therapies designed to exploit specific molecular pathways in aggressive cancers are an exciting area of current research. Mixed Lineage Leukemia (MLL) mutations such as the t(4;11) translocation cause aggressive leukemias that are refractory to conventional treatment. The t(4;11) translocation produces an MLL/AF4 fusion protein that activates key target genes through both epigenetic and transcriptional elongation mechanisms. In this study, we show that t(4;11) patient cells express high levels of BCL-2 and are highly sensitive to treatment with the BCL-2-specific BH3 mimetic ABT-199. We demonstrate that MLL/AF4 specifically upregulates the BCL-2 gene but not other BCL-2 family members via DOT1L-mediated H3K79me2/3. We use this information to show that a t(4;11) cell line is sensitive to a combination of ABT-199 and DOT1L inhibitors. In addition, ABT-199 synergizes with standard induction-type therapy in a xenotransplant model, advocating for the introduction of ABT-199 into therapeutic regimens for MLL-rearranged leukemias. AU - Benito, J.M.* AU - Godfrey, L.* AU - Kojima, K.* AU - Hogdal, L.* AU - Wunderlich, M.* AU - Geng, H.* AU - Marzo, I.* AU - Harutyunyan, K.G.* AU - Golfman, L.* AU - North, P.* AU - Kerry, J.* AU - Ballabio, E.* AU - Ni Chonghaile, T.* AU - Gonzalo, O.* AU - Qiu, Y.* AU - Jeremias, I. AU - Debose, L.* AU - O'Brien, E.T.* AU - Ma, H.C.* AU - Zhou, P.* AU - Jacamo, R.* AU - Park, E.* AU - Coombes, K.R.* AU - Zhang, N.* AU - Thomas, D.A.* AU - O'Brien, S.J.* AU - Kantarjian, H.M.* AU - Leverson, J.D.* AU - Kornblau, S.M.* AU - Andreeff, M.* AU - Mueschen, M.* AU - Zweidler-McKay, P.A.* AU - Mulloy, J.C.* AU - Letai, A.G.* AU - Milne, T.A.* AU - Konopleva, M.* C1 - 47716 C2 - 39607 SP - 2715-2727 TI - MLL-rearranged acute lymphoblastic leukemias activate BCL-2 through H3K79 methylation and are sensitive to the BCL-2-specific antagonist ABT-199. JO - Cell Rep. VL - 13 IS - 12 PY - 2015 SN - 2211-1247 ER - TY - JOUR AB - TRIM-NHL proteins are conserved among metazoans and control cell fate decisions in various stem cell linages. The Drosophila TRIM-NHL protein Brain tumor (Brat) directs differentiation of neuronal stem cells by suppressing self-renewal factors. Brat is an RNA-binding protein and functions as a translational repressor. However, it is unknown which RNAs Brat regulates and how RNA-binding specificity is achieved. Using RNA immunoprecipitation and RNAcompete, we identify Brat-bound mRNAs in Drosophila embryos and define consensus binding motifs for Brat as well as a number of additional TRIM-NHL proteins, indicating that TRIM-NHL proteins are conserved, sequence-specific RNA-binding proteins. We demonstrate that Brat-mediated repression and direct RNA-binding depend on the identified motif and show that binding of the localization factor Miranda to the Brat-NHL domain inhibits Brat activity. Finally, to unravel the sequence specificity of the NHL domain, we crystallize the Brat-NHL domain in complex with RNA and present a high-resolution protein-RNA structure of this fold. AU - Loedige, I.* AU - Jakob, L.* AU - Treiber, T.* AU - Ray, D.W.* AU - Stotz, M.* AU - Treiber, N.* AU - Hennig, J. AU - Cook, K.B.* AU - Morris, Q.* AU - Hughes, T.R.* AU - Engelmann, J.C.* AU - Krahn, M.P.* AU - Meister, G.* C1 - 47187 C2 - 39159 SP - 1206-1220 TI - The crystal structure of the NHL domain in complex with RNA reveals the molecular basis of Drosophila brain-tumor-mediated gene regulation. JO - Cell Rep. VL - 13 IS - 6 PY - 2015 SN - 2211-1247 ER - TY - JOUR AB - Exposure to low-dose irradiation causes transiently elevated expression of the long ncRNA PARTICLE (gene PARTICLE, promoter of MAT2A-antisense radiation-induced circulating lncRNA). PARTICLE affords both a cytosolic scaffold for the tumor suppressor methionine adenosyltransferase (MAT2A) and a nuclear genetic platform for transcriptional repression. In situ hybridization discloses that PARTICLE and MAT2A associate together following irradiation. Bromouridine tracing and presence in exosomes indicate intercellular transport, and this is supported by ex vivo data from radiotherapy-treated patients. Surface plasmon resonance indicates that PARTICLE forms a DNA-lncRNA triplex upstream of a MAT2A promoter CpG island. We show that PARTICLE represses MAT2A via methylation and demonstrate that the radiation-induced PARTICLE interacts with the transcription-repressive complex proteins G9a and SUZ12 (subunit of PRC2). The interplay of PARTICLE with MAT2A implicates this lncRNA in intercellular communication and as a recruitment platform for gene-silencing machineries through triplex formation in response to irradiation. AU - O'Leary, V.B. AU - Ovsepian, S.V.* AU - Carrascosa, L.G.* AU - Buske, F.A.* AU - Radulovic, V. AU - Niyazi, M.* AU - Mörtl, S. AU - Trau, M.* AU - Atkinson, M.J. AU - Anastasov, N. C1 - 44470 C2 - 36951 CY - Cambridge SP - 474-485 TI - PARTICLE, a triplex-forming long ncRNA, regulates locus-specific methylation in response to low-dose irradiation. JO - Cell Rep. VL - 11 IS - 3 PB - Cell Press PY - 2015 SN - 2211-1247 ER - TY - JOUR AB - Master regulators of the epithelial-mesenchymal transition such as Twist1 and Snail1 have been implicated in invasiveness and the generation of cancer stem cells, but their persistent activity inhibits stem-cell-like properties and the outgrowth of disseminated cancer cells into macroscopic metastases. Here, we show that Twist1 activation primes a subset of mammary epithelial cells for stem-cell-like properties, which only emerge and stably persist following Twist1 deactivation. Consequently, when cells undergo a mesenchymal-epithelial transition (MET), they do not return to their original epithelial cell state, evidenced by acquisition of invasive growth behavior and a distinct gene expression profile. These data provide an explanation for how transient Twist1 activation may promote all steps of the metastatic cascade; i.e., invasion, dissemination, and metastatic outgrowth at distant sites. AU - Schmidt, J. AU - Panzilius, E. AU - Bartsch, H.S.* AU - Irmler, M. AU - Beckers, J. AU - Kari, V.* AU - Linnemann, J. AU - Dragoi, D. AU - Hirschi, B. AU - Kloos, U. AU - Sass, S. AU - Theis, F.J. AU - Kahlert, S.* AU - Johnsen, S.A.* AU - Sotlar, K.* AU - Scheel, C. C1 - 43086 C2 - 36028 CY - Cambridge SP - 131-139 TI - Stem-cell-like properties and epithelial plasticity arise as stable traits after transient Twist1 activation. JO - Cell Rep. VL - 10 IS - 2 PB - Cell Press PY - 2015 SN - 2211-1247 ER - TY - JOUR AB - Mitochondrial production of reactive oxygen species (ROS) affects many processes in health and disease. SPG7 assembles with AFG3L2 into the mAAA protease at the inner membrane of mitochondria, degrades damaged proteins, and regulates the synthesis of mitochondrial ribosomes. SPG7 is cleaved and activated by AFG3L2 upon assembly. A variant in SPG7 that replaces arginine 688 with glutamine (Q688) is associated with several phenotypes, including toxicity of chemotherapeutic agents, type 2 diabetes mellitus, and (as reported here) coronary artery disease. We demonstrate that SPG7 processing is regulated by tyrosine phosphorylation of AFG3L2. Carriers of Q688 bypass this regulation and constitutively process and activate SPG7 mAAA protease. Cells expressing Q688 produce higher ATP levels and ROS, promoting cell proliferation. Our results thus reveal an unexpected link between the phosphorylation-dependent regulation of the mitochondria mAAA protease affecting ROS production and several clinical phenotypes. AU - Almontashiri, N.* AU - Chen, H.-H.* AU - Mailloux, R.* AU - Tatsuta, T* AU - Teng, A.* AU - Mahmoud, A* AU - Ho, T.* AU - Stewart, N.A.* AU - Rippstein, P.* AU - Harper, M.E.* AU - Roberts, R.* AU - Willenborg, C.* AU - Erdmann, J.* AU - CARDIoGRAM Consortium (Döring, A. AU - Illig, T. AU - Klopp, N. AU - Meisinger, C. AU - Meitinger, T. AU - Peters, A. AU - Wichmann, H.-E.) AU - Pastore, A.* AU - McBride, H.* AU - Langer, T.* AU - Stewart, A.F.R.* C1 - 31557 C2 - 34693 CY - Cambridge SP - 834-847 TI - SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes. JO - Cell Rep. VL - 7 IS - 3 PB - Cell Press PY - 2014 SN - 2211-1247 ER - TY - JOUR AB - The paracaspase Malt1 is a central regulator of antigen receptor signaling that is frequently mutated in human lymphoma. As a scaffold, it assembles protein complexes for NF-κB activation, and its proteolytic domain cleaves negative NF-κB regulators for signal enforcement. Still, the physiological functions of Malt1-protease are unknown. We demonstrate that targeted Malt1-paracaspase inactivation induces a lethal inflammatory syndrome with lymphocyte-dependent neurodegeneration in vivo. Paracaspase activity is essential for regulatory T cell (Treg) and innate-like B cell development, but it is largely dispensable for overcoming Malt1-dependent thresholds for lymphocyte activation. In addition to NF-κB inhibitors, Malt1 cleaves an entire set of mRNA stability regulators, including Roquin-1, Roquin-2, and Regnase-1, and paracaspase inactivation results in excessive interferon gamma (IFNγ) production by effector lymphocytes that drive pathology. Together, our results reveal distinct threshold and modulatory functions of Malt1 that differentially control lymphocyte differentiation and activation pathways and demonstrate that selective paracaspase blockage skews systemic immunity toward destructive autoinflammation. AU - Gewies, A.* AU - Gorka, O.* AU - Bergmann, H.* AU - Pechloff, K.* AU - Petermann, F.* AU - Jeltsch, K. AU - Rudelius, M.* AU - Kriegsmann, M.* AU - Weichert, W.* AU - Horsch, M. AU - Beckers, J. AU - Wurst, W. AU - Heikenwälder, M. AU - Korn, T.* AU - Heissmeyer, V. AU - Ruland, J.* C1 - 42802 C2 - 35363 SP - 1292-1305 TI - Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation. JO - Cell Rep. VL - 9 IS - 4 PY - 2014 SN - 2211-1247 ER - TY - JOUR AB - High-fat diets (HFDs) lead to obesity and inflammation in the central nervous system (CNS). Estrogens and estrogen receptor α (ERα) protect premenopausal females from the metabolic complications of inflammation and obesity-related disease. Here, we demonstrate that hypothalamic PGC-1α regulates ERα and inflammation in vivo. HFD significantly increased palmitic acid (PA) and sphingolipids in the CNS of male mice when compared to female mice. PA, in vitro, and HFD, in vivo, reduced PGC-1α and ERα in hypothalamic neurons and astrocytes of male mice and promoted inflammation. PGC-1α depletion with ERα overexpression significantly inhibited PA-induced inflammation, confirming that ERα is a critical determinant of the anti-inflammatory response. Physiologic relevance of ERα-regulated inflammation was demonstrated by reduced myocardial function in male, but not female, mice following chronic HFD exposure. Our findings show that HFD/PA reduces PGC-1α and ERα, promoting inflammation and decrements in myocardial function in a sex-specific way. AU - Morselli, E.* AU - Fuente-Martin, E. AU - Finan, B. AU - Kim, M.* AU - Frank, A.* AU - García-Cáceres, C. AU - Navas, C.R.* AU - Gordillo, R.* AU - Neinast, M.* AU - Paretzke, H.G.* AU - Li, D.L.* AU - Gao, Y. AU - Yi, C.-X. AU - Hahner, L.* AU - Palmer, B.F.* AU - Tschöp, M.H. AU - Clegg, D.J.* C1 - 34371 C2 - 35242 SP - 633-645 TI - Hypothalamic PGC-1α protects against high-fat diet exposure by regulating ERα. JO - Cell Rep. VL - 9 IS - 2 PY - 2014 SN - 2211-1247 ER - TY - JOUR AB - X-linked inhibitor of apoptosis protein (XIAP) has been identified as a potent regulator of innate immune responses, and loss-of-function mutations in XIAP cause the development of the X-linked lymphoproliferative syndrome type 2 (XLP-2) in humans. Using gene-targeted mice, we show that loss of XIAP or deletion of its RING domain lead to excessive cell death and IL-1β secretion from dendritic cells triggered by diverse Toll-like receptor stimuli. Aberrant IL-1β secretion is TNF dependent and requires RIP3 but is independent of cIAP1/cIAP2. The observed cell death also requires TNF and RIP3 but proceeds independently of caspase-1/caspase-11 or caspase-8 function. Loss of XIAP results in aberrantly elevated ubiquitylation of RIP1 outside of TNFR complex I. Virally infected Xiap(-/-) mice present with symptoms reminiscent of XLP-2. Our data show that XIAP controls RIP3-dependent cell death and IL-1β secretion in response to TNF, which might contribute to hyperinflammation in patients with XLP-2. AU - Yabal, M.* AU - Müller, N.* AU - Adler, H. AU - Knies, N.* AU - Groß, C.J.* AU - Damgaard, R.B.* AU - Kanegane, H.* AU - Ringelhan, M. AU - Kaufmann, T.* AU - Heikenwälder, M. AU - Strasser, A.* AU - Groß, O.* AU - Ruland, J.* AU - Peschel, C.* AU - Gyrd-Hansen, M.* AU - Jost, P.J.* C1 - 31532 C2 - 34550 CY - Cambridge SP - 1796-1808 TI - XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation. JO - Cell Rep. VL - 7 IS - 6 PB - Cell Press PY - 2014 SN - 2211-1247 ER - TY - JOUR AB - For years, the term "apoptosis" was used synonymously with programmed cell death. However, it was recently discovered that receptor interacting protein 3 (RIP3)-dependent "necroptosis" represents an alternative programmed cell death pathway activated in many inflamed tissues. Here, we show in a genetic model of chronic hepatic inflammation that activation of RIP3 limits immune responses and compensatory proliferation of liver parenchymal cells (LPC) by inhibiting Caspase-8-dependent activation of Jun-(N)-terminal kinase in LPC and nonparenchymal liver cells. In this way, RIP3 inhibits intrahepatic tumor growth and impedes the Caspase-8-dependent establishment of specific chromosomal aberrations that mediate resistance to tumor-necrosis-factor-induced apoptosis and underlie hepatocarcinogenesis. Moreover, RIP3 promotes the development of jaundice and cholestasis, because its activation suppresses compensatory proliferation of cholangiocytes and hepatic stem cells. These findings demonstrate a function of RIP3 in regulating carcinogenesis and cholestasis. Controlling RIP3 or Caspase-8 might represent a chemopreventive or therapeutic strategy against hepatocellular carcinoma and biliary disease. AU - Vucur, M.* AU - Reisinger, F. AU - Gautheron, J.* AU - Janssen, J.* AU - Roderburg, C.* AU - Cardenas, D.V.* AU - Kreggenwinkel, K.* AU - Koppe, C.* AU - Hammerich, L.* AU - Hakem, R.* AU - Unger, K. AU - Weber, A.* AU - Gassler, N.* AU - Luedde, M.* AU - Frey, N.* AU - Neumann, U.P.* AU - Tacke, F.* AU - Trautwein, C.* AU - Heikenwälder, M. AU - Luedde, T.* C1 - 27046 C2 - 32497 SP - 776-790 TI - RIP3 inhibits inflammatory hepatocarcinogenesis but promotes cholestasis by controlling caspase-8- and JNK-dependent compensatory cell proliferation. JO - Cell Rep. VL - 4 IS - 4 PB - Cell Press PY - 2013 SN - 2211-1247 ER - TY - JOUR AB - Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis. Moreover, vitamin B6 sensitizes cancer cells to apoptosis induction by distinct types of physical and chemical stress, including multiple chemotherapeutics. This effect requires pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. In line with a general role of vitamin B6 in stress responses, low PDXK expression levels were found to be associated with poor disease outcome in two independent cohorts of patients with NSCLC. These results indicate that PDXK expression levels constitute a biomarker for risk stratification among patients with NSCLC. AU - Galluzzi, L.* AU - Vitale, I.* AU - Senovilla, L.* AU - Olaussen, K.A.* AU - Pinna, G.* AU - Eisenberg, T.* AU - Goubar, A.* AU - Martins, I.* AU - Michels, J.* AU - Kratassiouk, G.* AU - Carmona-Gutierrez, D.* AU - Scoazec, M.* AU - Vacchelli, E.* AU - Schlemmer, F.* AU - Kepp, O.* AU - Shen, S.S.* AU - Tailler, M.* AU - Niso-Santano, M.* AU - Morselli, E.* AU - Criollo, A.* AU - Adjemian, S.* AU - Jemaa, M.* AU - Chaba, K.* AU - Pailleret, C.* AU - Michaud, M.* AU - Pietrocola, F.* AU - Tajeddine, N.* AU - Rouge, T.D.* AU - Araujo, N.* AU - Morozova, N.* AU - Robert, T.* AU - Ripoche, H.* AU - Commo, F.* AU - Besse, B.* AU - Validire, P.* AU - Fouret, P.* AU - Robin, A.* AU - Dorvault, N.* AU - Girard, P.* AU - Gouy, S.* AU - Pautier, P.* AU - Jägemann, N. AU - Nickel, A.C.* AU - Marsili, S.* AU - Paccard, C.* AU - Servant, N.* AU - Hupé, P.* AU - Behrens, C.* AU - Behnam-Motlagh, P.* AU - Kohno, K.* AU - Cremer, I.* AU - Damotte, D.* AU - Alifano, M.* AU - Midttun, O.* AU - Ueland, P.M.* AU - Lazar, V.* AU - Dessen, P.* AU - Zischka, H. AU - Chatelut, E.* AU - Castedo, M.* AU - Madeo, F.* AU - Barillot, E.* AU - Thomale, J.* AU - Wistuba, I.I.* AU - Sautes-Fridman, C.* AU - Zitvogel, L.* AU - Soria, J.C.* AU - Harel-Bellan, A.* AU - Kroemer, G.* C1 - 10892 C2 - 30441 SP - 257-269 TI - Prognostic impact of vitamin B6 metabolism in lung cancer. JO - Cell Rep. VL - 2 IS - 2 PB - Cell Press PY - 2012 SN - 2211-1247 ER - TY - JOUR AB - Excess serum free fatty acids (FFAs) are fundamental to the pathogenesis of insulin resistance. With high-fat feeding, FFAs activate NF-kappa B in target tissues, initiating negative crosstalk with insulin signaling. However, the mechanisms underlying FFA-dependent NF-kappa B activation remain unclear. Here, we demonstrate that the saturated FA, palmitate, requires Bcl10 for NF-kappa B activation in hepatocytes. Uptake of palmitate, metabolism to diacylglycerol, and subsequent activation of protein kinase C (PKC) appear to mechanistically link palmitate with Bcl10, known as a central component of a signaling complex that, along with CARMA3 and MALT1, activates NF-kappa B downstream of selected cell surface receptors. Consequently, Bcl10-deficient mice are protected from hepatic NF-kappa B activation and insulin resistance following brief high-fat diet, suggesting that Bcl10 plays a major role in the metabolic consequences of acute overnutrition. Surprisingly, while CARMA3 also participates in the palmitate response, MALT1 is completely dispensable, thereby revealing an apparent nonclassical role for Bcl10 in NF-kappa B signaling. AU - van Beek, M.* AU - Oravecz-Wilson, K.I.* AU - Delekta, P.C.* AU - Gu, S.F.* AU - Li, X.Q.* AU - Jin, X.H.* AU - Apel, I.J.* AU - Konkle, K.S.* AU - Feng, Y.J.* AU - Teitelbaum, D.H.* AU - Ruland, J. AU - McAllister-Lucas, L.M.* AU - Lucas, P.C.* C1 - 10894 C2 - 30440 SP - 444-452 TI - Bcl10 links saturated fat overnutrition with hepatocellular NF-κB activation and insulin resistance. JO - Cell Rep. VL - 1 IS - 5 PB - Cell Press PY - 2012 SN - 2211-1247 ER - TY - JOUR AB - Viruses can escape cytotoxic T cell (CTL) immunity by avoiding presentation of viral components via endogenous MHC class I antigen presentation in infected cells. Cross-priming of viral antigens circumvents such immune escape by allowing noninfected dendritic cells to activate virus-specific CTLs, but they remain ineffective against infected cells in which immune escape is functional. Here, we show that cross-presentation of antigen released from adenovirus-infected hepatocytes by liver sinusoidal endothelial cells stimulated cross-primed effector CTLs to release tumor necrosis factor (TNF), which killed virus-infected hepatocytes through caspase activation. TNF receptor signaling specifically eliminated infected hepatocytes that showed impaired anti-apoptotic defense. Thus, CTL immune surveillance against infection relies on two similarly important but distinct effector functions that are both MHC restricted, requiring either direct antigen recognition on target cells and canonical CTL effector function or cross-presentation and a noncanonical effector function mediated by TNF. AU - Wohlleber, D.* AU - Kashkar, H.* AU - Gärtner, K.* AU - Frings, M.K.* AU - Odenthal, M.* AU - Hegenbarth, S.* AU - Borner, C.* AU - Arnold, B.* AU - Hämmerling, G.* AU - Nieswandt, B.* AU - van Rooijen, N.* AU - Limmer, A.* AU - Cederbrant, K.* AU - Heikenwälder, M. AU - Pasparakis, M.* AU - Protzer, U. AU - Dienes, H.-P.* AU - Kurts, C.* AU - Krönke, M.* AU - Knolle, P.A.* C1 - 10891 C2 - 30445 SP - 478-487 TI - TNF-induced target cell killing by CTL activated through cross-presentation. JO - Cell Rep. VL - 2 IS - 3 PB - Cell Press PY - 2012 SN - 2211-1247 ER -