TY  - JOUR
AB  - Tight control of cGAS-STING-mediated DNA sensing is crucial to avoid auto-inflammation. The GTPase ADP-ribosylation factor 1 (ARF1) is crucial to maintain cGAS-STING homeostasis and various pathogenic ARF1 variants are associated with type I interferonopathies. Functional ARF1 inhibits STING activity by maintaining mitochondrial integrity and facilitating COPI-mediated retrograde STING trafficking and deactivation. Yet the factors governing the two distinct functions of ARF1 remained unexplored. Here, we dissect ARF1's dual role by a comparative analysis of disease-associated ARF1 variants and their impact on STING signalling. We identify a de novo heterozygous s.55 C > T/p.R19C ARF1 variant in a patient with type I interferonopathy symptoms. The GTPase-deficient variant ARF1 R19C selectively disrupts COPI binding and retrograde transport of STING, thereby prolonging innate immune activation without affecting mitochondrial integrity. Treatment of patient fibroblasts in vitro with the STING signalling inhibitors H-151 and amlexanox reduces chronic interferon signalling. Summarizing, our data reveal the molecular basis of a ARF1-associated type I interferonopathy allowing dissection of the two roles of ARF1, and suggest that pharmacological targeting of STING may alleviate ARF1-associated auto-inflammation.
AU  - Lang, J.*
AU  - Bergner, T.*
AU  - Zinngrebe, J.*
AU  - Lepelley, A.*
AU  - Vill, K.*
AU  - Leiz, S.*
AU  - Wlaschek, M.*
AU  - Wagner, M.
AU  - Scharffetter-Kochanek, K.*
AU  - Fischer-Posovszky, P.*
AU  - Read, C.*
AU  - Crow, Y.J.*
AU  - Hirschenberger, M.*
AU  - Sparrer, K.M.J.*
C1  - 73747
C2  - 57212
CY  - Campus, 4 Crinan St, London, N1 9xw, England
TI  - Distinct pathogenic mutations in ARF1 allow dissection of its dual role in cGAS-STING signalling.
JO  - EMBO Rep.
PB  - Springernature
PY  - 2025
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - The Epstein-Barr virus (EBV) nuclear antigen leader protein (EBNALP) is essential for the immortalization of naive B lymphocytes (NBLs). However, the mechanisms remain elusive. To understand EBNALP's role in B-cell transformation, we compare NBLs infected with wild-type EBV and an EBNALP-null mutant EBV using multi-omics techniques. EBNALP inactivation alters enhancer-promoter interactions, resulting in decreased CCND2 and increased CASP1 and BCL2L11 expression. Mechanistically, EBNALP interacts with and colocalizes with the looping factor YY1. Depletion of EBNALP reduces YY1 DNA-binding and enhancer-promoter interactions, similar to effects observed with YY1 depletion. Furthermore, EBNALP colocalizes with DPF2, a protein that binds to H3K14ac and H4K16ac. CRISPR depletion of DPF2 reduces both EBNALP and YY1 DNA binding, suggesting that the DPF2/EBNALP complex may tether YY1 to DNA to increase enhancer-promoter interactions. EBNALP inactivation also increases enhancer-promoter interactions at the CASP1 and BCL2L11 loci, along with elevated DPF2 and YY1 binding and DNA accessibility. Our data suggest that EBNALP regulates YY1 to rewire the host genome, which might facilitate naive B-cell transformation.
AU  - Wang, C.*
AU  - Leong, M.M.*
AU  - Ding, W.*
AU  - Narita, Y.*
AU  - Liu, X.*
AU  - Wang, H.*
AU  - Yiu, S.P.T.*
AU  - Lee, J.*
AU  - Zhao, K.R.S.*
AU  - Cui, A.*
AU  - Gewurz, B.*
AU  - Hammerschmidt, W.
AU  - Teng, M.*
AU  - Zhao, B.*
C1  - 72930
C2  - 56874
CY  - Campus, 4 Crinan St, London, N1 9xw, England
SP  - 810-835
TI  - Viral oncogene EBNALP regulates YY1 DNA binding and alters host 3D genome organization.
JO  - EMBO Rep.
VL  - 26
IS  - 3
PB  - Springernature
PY  - 2025
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Poly(ADP-ribose) polymerase 1 (PARP1) is one of the first responders to DNA damage and plays crucial roles in recruiting DNA repair proteins through its activity - poly(ADP-ribosyl)ation (PARylation). The enrichment of DNA repair proteins at sites of DNA damage has been described as the formation of a biomolecular condensate. However, it remains unclear how exactly PARP1 and PARylation contribute to the formation and organization of DNA repair condensates. Using recombinant human single-strand repair proteins in vitro, we find that PARP1 readily forms viscous biomolecular condensates in a DNA-dependent manner and that this depends on its three zinc finger (ZnF) domains. PARylation enhances PARP1 condensation in a PAR chain length-dependent manner and increases the internal dynamics of PARP1 condensates. DNA and single-strand break repair proteins XRCC1, LigIII, Polβ, and FUS partition in PARP1 condensates, although in different patterns. While Polβ and FUS are both homogeneously mixed within PARP1 condensates, FUS enrichment is greatly enhanced upon PARylation whereas Polβ partitioning is not. XRCC1 and LigIII display an inhomogeneous organization within PARP1 condensates; their enrichment in these multiphase condensates is enhanced by PARylation. Functionally, PARP1 condensates concentrate short DNA fragments, which correlates with PARP1 clusters compacting long DNA and bridging DNA ends. Furthermore, the presence of PARP1 condensates significantly promotes DNA ligation upon PARylation. These findings provide insight into how PARP1 condensation and PARylation regulate the assembly and biochemical activities of DNA repair factors, which may inform on how PARPs function in DNA repair foci and other PAR-driven condensates in cells.
AU  - Chin Sang, C.*
AU  - Moore, G.*
AU  - Tereshchenko, M.*
AU  - Zhang, H.*
AU  - Nosella, M.L.*
AU  - Dasovich, M.*
AU  - Alderson, T.R.
AU  - Leung, A.K.L.*
AU  - Finkelstein, I.J.*
AU  - Forman-Kay, J.D.*
AU  - Lee, H.O.*
C1  - 72231
C2  - 56512
TI  - PARP1 condensates differentially partition DNA repair proteins and enhance DNA ligation.
JO  - EMBO Rep.
PY  - 2024
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - The circular RNA (circRNA) Cdr1as is conserved across mammals and highly expressed in neurons, where it directly interacts with microRNA miR-7. However, the biological function of this interaction is unknown. Here, using primary cortical murine neurons, we demonstrate that stimulating neurons by sustained depolarization rapidly induces two-fold transcriptional upregulation of Cdr1as and strong post-transcriptional stabilization of miR-7. Cdr1as loss causes doubling of glutamate release from stimulated synapses and increased frequency and duration of local neuronal bursts. Moreover, the periodicity of neuronal networks increases, and synchronicity is impaired. Strikingly, these effects are reverted by sustained expression of miR-7, which also clears Cdr1as molecules from neuronal projections. Consistently, without Cdr1as, transcriptomic changes caused by miR-7 overexpression are stronger (including miR-7-targets downregulation) and enriched in secretion/synaptic plasticity pathways. Altogether, our results suggest that in cortical neurons Cdr1as buffers miR-7 activity to control glutamatergic excitatory transmission and neuronal connectivity important for long-lasting synaptic adaptations.
AU  - Georgii, E.
AU  - Woehler, A.*
AU  - Piwecka, M.*
AU  - Rajewsky, N.*
C1  - 70792
C2  - 55936
CY  - Campus, 4 Crinan St, London, N1 9xw, England
SP  - 3008-3039
TI  - miR-7 controls glutamatergic transmission and neuronal connectivity in a Cdr1as-dependent manner.
JO  - EMBO Rep.
VL  - 25
IS  - 7
PB  - Springernature
PY  - 2024
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Remnants of transposable elements (TEs) are widely expressed throughout mammalian embryo development. Originally infesting our genomes as selfish elements and acting as a source of genome instability, several of these elements have been co-opted as part of a complex system of genome regulation. Many TEs have lost transposition ability and their transcriptional potential has been tampered as a result of interactions with the host throughout evolutionary time. It has been proposed that TEs have been ultimately repurposed to function as gene regulatory hubs scattered throughout our genomes. In the early embryo in particular, TEs find a perfect environment of naïve chromatin to escape transcriptional repression by the host. As a consequence, it is thought that hosts found ways to co-opt TE sequences to regulate large-scale changes in chromatin and transcription state of their genomes. In this review, we discuss several examples of TEs expressed during embryo development, their potential for co-option in genome regulation and the evolutionary pressures on TEs and on our genomes.
AU  - Oomen, M.E.
AU  - Torres-Padilla, M.E.
C1  - 70398
C2  - 55604
CY  - Campus, 4 Crinan St, London, N1 9xw, England
SP  - 1721-1733
TI  - Jump-starting life: balancing transposable element co-option and genome integrity in the developing mammalian embryo.
JO  - EMBO Rep.
VL  - 25
IS  - 4
PB  - Springernature
PY  - 2024
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - In eukaryotes, DNA is packaged into chromatin with the help of highly conserved histone proteins. Together with DNA-binding proteins, posttranslational modifications (PTMs) on these histones play crucial roles in regulating genome function, cell fate determination, inheritance of acquired traits, cellular states, and diseases. While most studies have focused on individual DNA-binding proteins, chromatin proteins, or histone PTMs in bulk cell populations, such chromatin features co-occur and potentially act cooperatively to accomplish specific functions in a given cell. This review discusses state-of-the-art techniques for the simultaneous profiling of multiple chromatin features in low-input samples and single cells, focusing on histone PTMs, DNA-binding, and chromatin proteins. We cover the origins of the currently available toolkits, compare and contrast their characteristic features, and discuss challenges and perspectives for future applications. Studying the co-occurrence of histone PTMs, DNA-binding proteins, and chromatin proteins in single cells will be central for a better understanding of the biological relevance of combinatorial chromatin features, their impact on genomic output, and cellular heterogeneity.
AU  - Pepin, A.-S.
AU  - Schneider, R.
C1  - 71410
C2  - 56143
CY  - Campus, 4 Crinan St, London, N1 9xw, England
SP  - 3202-3220
TI  - Emerging toolkits for decoding the co-occurrence of modified histones and chromatin proteins.
JO  - EMBO Rep.
VL  - 25
IS  - 8
PB  - Springernature
PY  - 2024
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - An issue with the selection of files related to Table EV1 wasidentified during the publication process. Table EV1 is corrected. Expanded view data, supplementary information, appendices are available for this paper at https://doi.org/10.1038/s44319-024-00269-5.
AU  - Pepin, A.-S.
AU  - Schneider, R.
C1  - 71962
C2  - 56300
SP  - 3202–3220
TI  - Publisher Correction: Emerging toolkits for decoding the co-occurrence of modified histones and chromatin proteins.
JO  - EMBO Rep.
PY  - 2024
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - The centromere, defined by the enrichment of CENP-A (a Histone H3 variant) containing nucleosomes, is a specialised chromosomal locus that acts as a microtubule attachment site. To preserve centromere identity, CENP-A levels must be maintained through active CENP-A loading during the cell cycle. A central player mediating this process is the Mis18 complex (Mis18α, Mis18β and Mis18BP1), which recruits the CENP-A-specific chaperone HJURP to centromeres for CENP-A deposition. Here, using a multi-pronged approach, we characterise the structure of the Mis18 complex and show that multiple hetero- and homo-oligomeric interfaces facilitate the hetero-octameric Mis18 complex assembly composed of 4 Mis18α, 2 Mis18β and 2 Mis18BP1. Evaluation of structure-guided/separation-of-function mutants reveals structural determinants essential for cell cycle controlled Mis18 complex assembly and centromere maintenance. Our results provide new mechanistic insights on centromere maintenance, highlighting that while Mis18α can associate with centromeres and deposit CENP-A independently of Mis18β, the latter is indispensable for the optimal level of CENP-A loading required for preserving the centromere identity.
AU  - Thamkachy, R.*
AU  - Medina-Pritchard, B.*
AU  - Park, S.H.*
AU  - Chiodi, C.G.*
AU  - Zou, J.*
AU  - de la Torre-Barranco, M.*
AU  - Shimanaka, K.*
AU  - Abad, M.A.*
AU  - Gallego Páramo, C.*
AU  - Feederle, R.
AU  - Ruksenaite, E.*
AU  - Heun, P.*
AU  - Davies, O.R.*
AU  - Rappsilber, J.*
AU  - Schneidman-Duhovny, D.*
AU  - Cho, U.S.*
AU  - Jeyaprakash, A.A.*
C1  - 71028
C2  - 55990
CY  - Campus, 4 Crinan St, London, N1 9xw, England
TI  - Structural basis for Mis18 complex assembly and its implications for centromere maintenance.
JO  - EMBO Rep.
PB  - Springernature
PY  - 2024
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Accumulation of excess nutrients hampers proper liver function and is linked to nonalcoholic fatty liver disease (NAFLD) in obesity. However, the signals responsible for an impaired adaptation of hepatocytes to obesogenic dietary cues remain still largely unknown. Post-translational modification by the small ubiquitin-like modifier (SUMO) allows for a dynamic regulation of numerous processes including transcriptional reprogramming. We demonstrate that specific SUMOylation of transcription factor Prox1 represents a nutrient-sensitive determinant of hepatic fasting metabolism. Prox1 is highly SUMOylated on lysine 556 in the liver of ad libitum and refed mice, while this modification is abolished upon fasting. In the context of diet-induced obesity, Prox1 SUMOylation becomes less sensitive to fasting cues. The hepatocyte-selective knock-in of a SUMOylation-deficient Prox1 mutant into mice fed a high-fat/high-fructose diet leads to a reduction of systemic cholesterol levels, associated with the induction of liver bile acid detoxifying pathways during fasting. The generation of tools to maintain the nutrient-sensitive SUMO-switch on Prox1 may thus contribute to the development of "fasting-based" approaches for the preservation of metabolic health.
AU  - Alfaro, A.J.
AU  - Dittner, C.*
AU  - Becker, J.*
AU  - Loft, A.
AU  - Mhamane, A.
AU  - Maida, A.
AU  - Georgiadi, A.
AU  - Tsokanos, F.-F.
AU  - Klepac, K.
AU  - Molocea, C.-E.
AU  - El-Merahbi, R.
AU  - Motzler, K.
AU  - Geppert, J.
AU  - Karikari, R.A.
AU  - Szendrödi, J.*
AU  - Feuchtinger, A.
AU  - Hofmann, S.M.
AU  - Karaca, S.*
AU  - Urlaub, H.*
AU  - Berriel Diaz, M.
AU  - Melchior, F.*
AU  - Herzig, S.
C1  - 68011
C2  - 54489
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Fasting-sensitive SUMO-switch on Prox1 controls hepatic cholesterol metabolism.
JO  - EMBO Rep.
VL  - 24
IS  - 10
PB  - Wiley
PY  - 2023
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - The use of beneficial microbes to mitigate drought stress tolerance of plants is of great potential albeit little understood. We show here that a root endophytic desert bacterium, Pseudomonas argentinensis strain SA190, enhances drought stress tolerance in Arabidopsis. Transcriptome and genetic analysis demonstrate that SA190-induced root morphogenesis and gene expression is mediated via the plant abscisic acid (ABA) pathway. Moreover, we demonstrate that SA190 primes the promoters of target genes in an epigenetic ABA-dependent manner. Application of SA190 priming on crops is demonstrated for alfalfa, showing enhanced performance under drought conditions. In summary, a single beneficial root bacterial strain can help plants to resist drought conditions.
AU  - Alwutayd, K.M.*
AU  - Rawat, A.A.*
AU  - Sheikh, A.H.*
AU  - Almeida-Trapp, M.*
AU  - Veluchamy, A.*
AU  - Jalal, R.*
AU  - Karampelias, M.*
AU  - Froehlich, K.*
AU  - Alzaed, W.*
AU  - Tabassum, N.*
AU  - Rabelo Schley, T.
AU  - Schäffner, A.
AU  - Daur, I.*
AU  - Saad, M.M.*
AU  - Hirt, H.*
C1  - 67847
C2  - 54325
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Microbe-induced drought tolerance by ABA-mediated root architecture and epigenetic reprogramming.
JO  - EMBO Rep.
VL  - 24
IS  - 8
PB  - Wiley
PY  - 2023
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Mouse embryonic stem cells (ESCs) display pluripotency features characteristic of the inner cell mass of the blastocyst. Mouse embryonic stem cell cultures are highly heterogeneous and include a rare population of cells, which recapitulate characteristics of the 2-cell embryo, referred to as 2-cell-like cells (2CLCs). Whether and how ESC and 2CLC respond to environmental cues has not been fully elucidated. Here, we investigate the impact of mechanical stress on the reprogramming of ESC to 2CLC. We show that hyperosmotic stress induces 2CLC and that this induction can occur even after a recovery time from hyperosmotic stress, suggesting a memory response. Hyperosmotic stress in ESCs leads to accumulation of reactive-oxygen species (ROS) and ATR checkpoint activation. Importantly, preventing either elevated ROS levels or ATR activation impairs hyperosmotic-mediated 2CLC induction. We further show that ROS generation and the ATR checkpoint act within the same molecular pathway in response to hyperosmotic stress to induce 2CLCs. Altogether, these results shed light on the response of ESC to mechanical stress and on our understanding of 2CLC reprogramming.
AU  - Canat, A.
AU  - Atilla, D.
AU  - Torres-Padilla, M.E.
C1  - 68121
C2  - 54599
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Hyperosmotic stress induces 2-cell-like cells through ROS and ATR signaling.
JO  - EMBO Rep.
VL  - 24
IS  - 9
PB  - Wiley
PY  - 2023
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Adipocytes are critical regulators of metabolism and energy balance. While white adipocyte dysfunction is a hallmark of obesity-associated disorders, thermogenic adipocytes are linked to cardiometabolic health. As adipocytes dynamically adapt to environmental cues by functionally switching between white and thermogenic phenotypes, a molecular understanding of this plasticity could help improving metabolism. Here, we show that the lncRNA Apoptosis associated transcript in bladder cancer (AATBC) is a human-specific regulator of adipocyte plasticity. Comparing transcriptional profiles of human adipose tissues and cultured adipocytes we discovered that AATBC was enriched in thermogenic conditions. Using primary and immortalized human adipocytes we found that AATBC enhanced the thermogenic phenotype, which was linked to increased respiration and a more fragmented mitochondrial network. Expression of AATBC in adipose tissue of mice led to lower plasma leptin levels. Interestingly, this association was also present in human subjects, as AATBC in adipose tissue was inversely correlated with plasma leptin levels, BMI, and other measures of metabolic health. In conclusion, AATBC is a novel obesity-linked regulator of adipocyte plasticity and mitochondrial function in humans.
AU  - Giroud, M.
AU  - Kotschi, S.*
AU  - Kwon, Y.
AU  - Le Thuc, O.
AU  - Hoffmann, A.
AU  - Gil Lozano, M.
AU  - Karbiener, M.*
AU  - Higareda-Almaraz, J.
AU  - Khani, S.
AU  - Tews, D.*
AU  - Fischer-Posovszky, P.*
AU  - Sun, W.*
AU  - Dong, H.*
AU  - Ghosh, A.*
AU  - Wolfrum, C.*
AU  - Wabitsch, M.*
AU  - Virtanen, K.A.*
AU  - Blüher, M.
AU  - Nielsen, S.*
AU  - Zeigerer, A.
AU  - García-Cáceres, C.
AU  - Scheideler, M.
AU  - Herzig, S.
AU  - Bartelt, A.
C1  - 68316
C2  - 54735
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - The obesity-linked human lncRNA AATBC stimulates mitochondrial function in adipocytes.
JO  - EMBO Rep.
VL  - 24
IS  - 10
PB  - Wiley
PY  - 2023
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - The largest subunit of RNA polymerase (Pol) II harbors an evolutionarily conserved C-terminal domain (CTD), composed of heptapeptide repeats, central to the transcriptional process. Here, we analyze the transcriptional phenotypes of a CTD-Δ5 mutant that carries a large CTD truncation in human cells. Our data show that this mutant can transcribe genes in living cells but displays a pervasive phenotype with impaired termination, similar to but more severe than previously characterized mutations of CTD tyrosine residues. The CTD-Δ5 mutant does not interact with the Mediator and Integrator complexes involved in the activation of transcription and processing of RNAs. Examination of long-distance interactions and CTCF-binding patterns in CTD-Δ5 mutant cells reveals no changes in TAD domains or borders. Our data demonstrate that the CTD is largely dispensable for the act of transcription in living cells. We propose a model in which CTD-depleted Pol II has a lower entry rate onto DNA but becomes pervasive once engaged in transcription, resulting in a defect in termination.
AU  - Yahia, Y.*
AU  - Pigeot, A.*
AU  - El Aabidine, A.Z.*
AU  - Shah, N.
AU  - Karasu, N.*
AU  - Forne, I.*
AU  - Krebs, S.*
AU  - Blum, H.*
AU  - Esnault, C.*
AU  - Sexton, T.*
AU  - Imhof, A.*
AU  - Eick, D.
AU  - Andrau, J.C.*
C1  - 68132
C2  - 54610
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - RNA polymerase II CTD is dispensable for transcription and required for termination in human cells.
JO  - EMBO Rep.
VL  - 24
IS  - 9
PB  - Wiley
PY  - 2023
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - According to the current consensus, murine neural stem cells (NSCs) apically contacting the lateral ventricle generate differentiated progenitors by rare asymmetric divisions or by relocating to the basal side of the ventricular-subventricular zone (V-SVZ). Both processes will ultimately lead to the generation of adult-born olfactory bulb (OB) interneurons. In contrast to this view, we here find that adult-born OB interneurons largely derive from an additional NSC-type resident in the basal V-SVZ. Despite being both capable of self-renewal and long-term quiescence, apical and basal NSCs differ in Nestin expression, primary cilia extension and frequency of cell division. The expression of Notch-related genes also differs between the two NSC groups, and Notch activation is greatest in apical NSCs. Apical downregulation of Notch-effector Hes1 decreases Notch activation while increasing proliferation across the niche and neurogenesis from apical NSCs. Underscoring their different roles in neurogenesis, lactation-dependent increase in neurogenesis is paralleled by extra activation of basal but not apical NSCs. Thus, basal NSCs support OB neurogenesis, whereas apical NSCs impart Notch-mediated lateral inhibition across the V-SVZ.
AU  - Baur, K.*
AU  - Abdullah, Y.*
AU  - Mandl, C.*
AU  - Hölzl-Wenig, G.*
AU  - Shi, Y.*
AU  - Edelkraut, U.*
AU  - Khatri, P.*
AU  - Hagenston, A.M.*
AU  - Irmler, M.
AU  - Beckers, J.
AU  - Ciccolini, F.*
C1  - 65761
C2  - 52470
TI  - A novel stem cell type at the basal side of the subventricular zone maintains adult neurogenesis.
JO  - EMBO Rep.
PY  - 2022
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - The severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) is the causative agent of COVID-19, but host cell factors contributing to COVID-19 pathogenesis remain only partly understood. We identify the host metalloprotease ADAM17 as a facilitator of SARS-CoV-2 cell entry and the metalloprotease ADAM10 as a host factor required for lung cell syncytia formation, a hallmark of COVID-19 pathology. ADAM10 and ADAM17, which are broadly expressed in the human lung, cleave the SARS-CoV-2 spike protein (S) in vitro, indicating that ADAM10 and ADAM17 contribute to the priming of S, an essential step for viral entry and cell fusion. ADAM protease-targeted inhibitors severely impair lung cell infection by the SARS-CoV-2 variants of concern alpha, beta, delta, and omicron and also reduce SARS-CoV-2 infection of primary human lung cells in a TMPRSS2 protease-independent manner. Our study establishes ADAM10 and ADAM17 as host cell factors for viral entry and syncytia formation and defines both proteases as potential targets for antiviral drug development.
AU  - Jocher, G.*
AU  - Grass, V.*
AU  - Tschirner, S.K.*
AU  - Riepler, L.*
AU  - Breimann, S.*
AU  - Kaya, T.*
AU  - Oelsner, M.
AU  - Hamad, M.S.*
AU  - Hofmann, L.I.*
AU  - Blobel, C.P.*
AU  - Schmidt-Weber, C.B.
AU  - Gokce, O.*
AU  - Jakwerth, C.A.
AU  - Trimpert, J.*
AU  - Kimpel, J.*
AU  - Pichlmair, A.*
AU  - Lichtenthaler, S.F.*
C1  - 64969
C2  - 52592
TI  - ADAM10 and ADAM17 promote SARS-CoV-2 cell entry and spike protein-mediated lung cell fusion.
JO  - EMBO Rep.
VL  - 23
IS  - 6
PY  - 2022
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Immunoregulation of inflammatory, infection-triggered processes in the brain constitutes a central mechanism to control devastating disease manifestations such as epilepsy. Observational studies implicate the viability of Taenia solium cysts as key factor determining severity of neurocysticercosis (NCC), the most common cause of epilepsy, especially in children, in Sub-Saharan Africa. Viable, in contrast to decaying, cysts mostly remain clinically silent by yet unknown mechanisms, potentially involving Tregs in controlling inflammation. Here, we show that glutamate dehydrogenase from viable cysts instructs tolerogenic monocytes to release IL-10 and the lipid mediator PGE2. These act in concert, converting naive CD4+ T cells into CD127−CD25hiFoxP3+CTLA-4+ Tregs, through the G protein-coupled receptors EP2 and EP4 and the IL-10 receptor. Moreover, while viable cyst products strongly upregulate IL-10 and PGE2 transcription in microglia, intravesicular fluid, released during cyst decay, induces pro-inflammatory microglia and TGF-β as potential drivers of epilepsy. Inhibition of PGE2 synthesis and IL-10 signaling prevents Treg induction by viable cyst products. Harnessing the PGE2-IL-10 axis and targeting TGF-ß signaling may offer an important therapeutic strategy in inflammatory epilepsy and NCC.
AU  - Prodjinotho, U.F.*
AU  - Gres, V.*
AU  - Henkel, F.
AU  - Lacorcia, M.*
AU  - Dandl, R.*
AU  - Haslbeck, M.*
AU  - Schmidt, V.*
AU  - Winkler, A.S.*
AU  - Sikasunge, C.*
AU  - Jakobsson, P.J.*
AU  - Henneke, P.*
AU  - Esser-von Bieren, J.
AU  - Prazeres da Costa, C.U.*
C1  - 64745
C2  - 52432
TI  - Helminthic dehydrogenase drives PGE2 and IL-10 production in monocytes to potentiate Treg induction.
JO  - EMBO Rep.
VL  - 23
IS  - 5
PY  - 2022
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Fine-tuned dissolution of pluripotency is critical for proper cell differentiation. Here we show that the mesodermal transcription factor, T, globally affects the properties of pluripotency through binding to Oct4 and to the loci of other pluripotency regulators. Strikingly, lower T levels coordinately affect naïve pluripotency, thereby directly activating the germ cell differentiation program, in contrast to the induction of germ cell fate of primed models. Contrary to the effect of lower T levels, higher T levels more severely affect the pluripotency state, concomitantly enhancing the somatic differentiation program and repressing the germ cell differentiation program. Consistent with such in vitro findings, nascent germ cells in vivo are detected in the region of lower T levels at the posterior primitive streak. Furthermore, T and core pluripotency regulators co-localize at the loci of multiple germ cell determinants responsible for germ cell development. In conclusion, our findings indicate that residual pluripotency establishes the earliest and fundamental regulatory mechanism for inductive germline segregation from somatic lineages.
AU  - Aramaki, S.*
AU  - Kagiwada, S.*
AU  - Wu, G.*
AU  - Obridge, D.*
AU  - Adachi, K.*
AU  - Kutejova, E.*
AU  - Lickert, H.
AU  - Hübner, K.*
AU  - Schöler, H.R.*
C1  - 62306
C2  - 50763
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Residual pluripotency is required for inductive germ cell segregation.
JO  - EMBO Rep.
PB  - Wiley
PY  - 2021
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - The recruitment of thermogenic brite adipocytes within white adipose tissue attenuates obesity and metabolic comorbidities, arousing interest in understanding the underlying regulatory mechanisms. The molecular network of brite adipogenesis, however, remains largely unresolved. In this light, long noncoding RNAs (lncRNAs) emerged as a versatile class of modulators that control many steps within the differentiation machinery. Leveraging the naturally varying propensities of different inbred mouse strains for white adipose tissue browning, we identify the nuclear lncRNA Ctcflos as a pivotal orchestrator of thermogenic gene expression during brite adipocyte differentiation. Mechanistically, Ctcflos acts as a pleiotropic regulator, being essential for the transcriptional recruitment of the early core thermogenic regulatory program and the modulation of alternative splicing to drive brite adipogenesis. This is showcased by Ctcflos-regulated gene transcription and splicing of the key browning factor Prdm16 toward the isoform that is specific for the thermogenic gene program. Conclusively, our findings emphasize the mechanistic versatility of lncRNAs acting at several independent levels of gene expression for effective regulation of key differentiation factors to direct cell fate and function.
AU  - Bast-Habersbrunner, A.*
AU  - Kiefer, C.*
AU  - Weber, P.
AU  - Fromme, T.*
AU  - Schießl, A.*
AU  - Schwalie, P.C.*
AU  - Deplancke, B.*
AU  - Li, Y.*
AU  - Klingenspor, M.*
C1  - 62177
C2  - 50680
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - LncRNA Ctcflos orchestrates transcription and alternative splicing in thermogenic adipogenesis.
JO  - EMBO Rep.
PB  - Wiley
PY  - 2021
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - In eukaryotic cells, DNA is tightly packed with the help of histone proteins into chromatin. Chromatin architecture can be modified by various post-translational modifications of histone proteins. For almost 60 years now, studies on histone lysine acetylation have unraveled the contribution of this acylation to an open chromatin state with increased DNA accessibility, permissive for gene expression. Additional complexity emerged from the discovery of other types of histone lysine acylations. The acyl group donors are products of cellular metabolism, and distinct histone acylations can link the metabolic state of a cell with chromatin architecture and contribute to cellular adaptation through changes in gene expression. Currently, various technical challenges limit our full understanding of the actual impact of most histone acylations on chromatin dynamics and of their biological relevance. In this review, we summarize the state of the art and provide an overview of approaches to overcome these challenges. We further discuss the concept of subnuclear metabolic niches that could regulate local CoA availability and thus couple cellular metabolisms with the epigenome.
AU  - Nitsch, S.
AU  - Zorro Shahidian, L.
AU  - Schneider, R.
C1  - 62371
C2  - 50698
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Histone acylations and chromatin dynamics: Concepts, challenges, and links to metabolism.
JO  - EMBO Rep.
VL  - 22
IS  - 7
PB  - Wiley
PY  - 2021
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Hepatitis B virus (HBV) persists by depositing a covalently closed circular DNA (cccDNA) in the nucleus of infected cells that cannot be targeted by available antivirals. Interferons can diminish HBV cccDNA via APOBEC3-mediated deamination. Here, we show that overexpression of APOBEC3A alone is not sufficient to reduce HBV cccDNA that requires additional treatment of cells with interferon indicating involvement of an interferon-stimulated gene (ISG) in cccDNA degradation. Transcriptome analyses identify ISG20 as the only type I and II interferon-induced, nuclear protein with annotated nuclease activity. ISG20 localizes to nucleoli of interferon-stimulated hepatocytes and is enriched on deoxyuridine-containing single-stranded DNA that mimics transcriptionally active, APOBEC3A-deaminated HBV DNA. ISG20 expression is detected in human livers in acute, self-limiting but not in chronic hepatitis B. ISG20 depletion mitigates the interferon-induced loss of cccDNA, and co-expression with APOBEC3A is sufficient to diminish cccDNA. In conclusion, non-cytolytic HBV cccDNA decline requires the concerted action of a deaminase and a nuclease. Our findings highlight that ISGs may cooperate in their antiviral activity that may be explored for therapeutic targeting.
AU  - Stadler, D.
AU  - Kächele, M.
AU  - Jones, A.
AU  - Hess J.
AU  - Urban, C.
AU  - Schneider, J.
AU  - Xia, Y.
AU  - Oswald, A.
AU  - Nebioglu, F.*
AU  - Bester, R.
AU  - Lasitschka, F.*
AU  - Ringelhan, M.
AU  - Ko, C.
AU  - Chou, W.M.
AU  - Geerlof, A.
AU  - van de Klundert, M.
AU  - Wettengel, J.M.
AU  - Schirmacher, P.*
AU  - Heikenwälder, M.*
AU  - Schreiner, S.
AU  - Bartenschlager, R.*
AU  - Pichlmair, A.
AU  - Sattler, M.
AU  - Unger, K.
AU  - Protzer, U.
C1  - 62017
C2  - 50592
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Interferon-induced degradation of the persistent hepatitis B virus cccDNA form depends on ISG20.
JO  - EMBO Rep.
VL  - 22
IS  - 6
PB  - Wiley
PY  - 2021
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - While Epstein-Barr virus (EBV) establishes a life-long latent infection in apparently healthy human immunocompetent hosts, immunodeficient individuals are at particular risk to develop lymphoproliferative B-cell malignancies caused by EBV. A key EBV protein is the transcription factor EBV nuclear antigen 2 (EBNA2), which initiates B-cell proliferation. Here, we combine biochemical, cellular, and in vivo experiments demonstrating that the mitotic polo-like kinase 1 (PLK1) binds to EBNA2, phosphorylates its transactivation domain, and thereby inhibits its biological activity. EBNA2 mutants that impair PLK1 binding or prevent EBNA2 phosphorylation are gain-of-function mutants. They exhibit enhanced transactivation capacities, accelerate the proliferation of infected B cells, and promote the development of monoclonal B-cell lymphomas in infected mice. Thus, PLK1 coordinates the activity of EBNA2 to attenuate the risk of tumor incidences in favor of the establishment of latency in the infected but healthy host.
AU  - Zhang, X.
AU  - Schuhmachers, P.*
AU  - Mourao, A.
AU  - Giansanti, P.*
AU  - Murer, A.*
AU  - Thumann, S.
AU  - Kuklik-Roos, C.
AU  - Beer, S.
AU  - Hauck, S.M.
AU  - Hammerschmidt, W.
AU  - Kuppers, R.*
AU  - Kuster, B.*
AU  - Raab, M.*
AU  - Strebhardt, K.*
AU  - Sattler, M.
AU  - Münz, C.*
AU  - Kempkes, B.
C1  - 63175
C2  - 51367
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - PLK1-dependent phosphorylation restrains EBNA2 activity and lymphomagenesis in EBV-infected mice.
JO  - EMBO Rep.
PB  - Wiley
PY  - 2021
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Histone post-translational modifications (PTMs) are key players in chromatin regulation. The identification of novel histone acylations raises important questions regarding their role in transcription. In this study, we characterize the role of an acylation on the lateral surface of the histone octamer, H3K122 succinylation (H3K122succ), in chromatin function and transcription. Using chromatin succinylated at H3K122 in in vitro transcription assays, we show that the presence of H3K122succ is sufficient to stimulate transcription. In line with this, we found in our ChIP assays H3K122succ enriched on promoters of active genes and H3K122succ enrichment scaling with gene expression levels. Furthermore, we show that the co-activators p300/CBP can succinylate H3K122 and identify sirtuin 5 (SIRT5) as a new desuccinylase. By applying single molecule FRET assays, we demonstrate a direct effect of H3K122succ on nucleosome stability, indicating an important role for histone succinylation in modulating chromatin dynamics. Together, these data provide the first insights into the mechanisms underlying transcriptional regulation by H3K122succ.
AU  - Zorro Shahidian, L.
AU  - Haas, M.*
AU  - Le Gras, S.*
AU  - Nitsch, S.
AU  - Mourao, A.
AU  - Geerlof, A.
AU  - Margueron, R.*
AU  - Michaelis, J.*
AU  - Daujat, S.*
AU  - Schneider, R.
C1  - 61150
C2  - 50067
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Succinylation of H3K122 destabilizes nucleosomes and enhances transcription.
JO  - EMBO Rep.
VL  - 22
IS  - 3
PB  - Wiley
PY  - 2021
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - We here address the question whether the unique capacity of mesenchymal stem cells to re-establish tissue homeostasis depends on their potential to sense pathogen-associated molecular pattern and, in consequence, mount an adaptive response in the interest of tissue repair. After injection of MSCs primed with the bacterial wall component LPS into murine wounds, an unexpected acceleration of healing occurs, clearly exceeding that of non-primed MSCs. This correlates with a fundamental reprogramming of the transcriptome in LPS-treated MSCs as deduced from RNAseq analysis and its validation. A network of genes mediating the adaptive response through the Toll-like receptor 4 (TLR4) pathway responsible for neutrophil and macrophage recruitment and their activation profoundly contributes to enhanced wound healing. In fact, injection of LPS-primed MSCs silenced for TLR4 fails to accelerate wound healing. These unprecedented findings hold substantial promise to refine current MSC-based therapies for difficult-to-treat wounds.
AU  - Munir, S.*
AU  - Basu, A.*
AU  - Maity, P.*
AU  - Krug, L.*
AU  - Haas, P.*
AU  - Jiang, D.
AU  - Strauss, G.*
AU  - Wlaschek, M.*
AU  - Geiger, H.*
AU  - Singh, K.*
AU  - Scharffetter-Kochanek, K.*
C1  - 58652
C2  - 48591
TI  - TLR4-dependent shaping of the wound site by MSCs accelerates wound healing.
JO  - EMBO Rep.
VL  - 21
IS  - 5
PY  - 2020
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Pluripotent stem cells are thought of as a surrogate of early developmental stages that sustain the capacity to generate all cell types in the body, thereby constituting an invaluable tool to address the mechanisms underlying cellular plasticity. In the mouse, cells resembling totipotent 2-cell-stage embryos (2-cell-like cells) arise at a very low frequency in embryonic stem cell (ESC) cultures. However, the extent to which these early-embryonic-like cells recapitulate the molecular features of the early embryo is unclear. Here, we have undertaken a characterization of some of the metabolic features of early-embryonic-like cells in culture. Our data indicate that early-embryonic-like cells exhibit decreased glycolytic and respiratory activity, lower levels of reactive oxygen species and increased glucose uptake, suggesting a shift of the metabolic programme during 2-cell-like cell reprogramming. Accordingly, we find that 2-cell-like cells can be induced by defined metabolites. Thus, in addition to their transcriptional and chromatin features, 2-cell-like cells recapitulate some of the metabolic features of their in vivo counterpart. Altogether, our work underscores a distinct metabolic state of early-embryonic-like cells and identifies compounds that can induce their emergence in vitro.
AU  - Rodriguez-Terrones, D.
AU  - Hartleben, G.
AU  - Gaume, X.
AU  - Eid, A.
AU  - Guthmann, M.
AU  - Iturbide Martinez De Albeniz, A.
AU  - Torres-Padilla, M.E.
C1  - 57659
C2  - 47944
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - A distinct metabolic state arises during the emergence of 2-cell-like cells.
JO  - EMBO Rep.
VL  - 21
IS  - 1
PB  - Wiley
PY  - 2020
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Abnormal generation of neurotoxic amyloid-beta peptide (A beta) 42/43 species due to mutations in the catalytic presenilin 1 (PS1) subunit of gamma-secretase is the major cause of familial Alzheimer's disease (FAD). Deeper mechanistic insight on the generation of A beta 43 is still lacking, and it is unclear whether gamma-secretase modulators (GSMs) can reduce the levels of this A beta species. By comparing several types of A beta 43-generating FAD mutants, we observe that very high levels of A beta 43 are often produced when presenilin function is severely impaired. Altered interactions of C99, the precursor of A beta, are found for all mutants and are independent of their particular effect on A beta production. Furthermore, unlike previously described GSMs, the novel compound RO7019009 can effectively lower A beta 43 production of all mutants. Finally, substrate-binding competition experiments suggest that RO7019009 acts mechanistically after initial C99 binding. We conclude that altered C99 interactions are a common feature of diverse types of PS1 FAD mutants and that also patients with A beta 43-generating FAD mutations could in principle be treated by GSMs.
AU  - Trambauer, J.*
AU  - Rodríguez Sarmiento, R.M.*
AU  - Fukumori, A.*
AU  - Feederle, R.
AU  - Baumann, K.*
AU  - Steiner, H.*
C1  - 57418
C2  - 47790
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - A beta 43-producing PS1 FAD mutants cause altered substrate interactions and respond to gamma-secretase modulation.
JO  - EMBO Rep.
VL  - 21
IS  - 1
PB  - Wiley
PY  - 2020
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Single nucleotide polymorphisms (SNPs) inTMEM106Bencoding the lysosomal typeIItransmembrane protein 106B increase the risk for frontotemporal lobar degeneration (FTLD) ofGRN(progranulin gene) mutation carriers. Currently, it is unclear if progranulin (PGRN) andTMEM106B are synergistically linked and if a gain or a loss of function ofTMEM106B is responsible for the increased disease risk of patients withGRNhaploinsufficiency. We therefore compare behavioral abnormalities, gene expression patterns, lysosomal activity, andTDP-43 pathology in single and double knockout animals.Grn(-/-)/Tmem106b(-/-)mice show a strongly reduced life span and massive motor deficits. Gene expression analysis reveals an upregulation of molecular signature characteristic for disease-associated microglia and autophagy. Dysregulation of maturation of lysosomal proteins as well as an accumulation of ubiquitinated proteins and widespread p62 deposition suggest that proteostasis is impaired. Moreover, while singleGrn(-/-)knockouts only occasionally showTDP-43 pathology, the double knockout mice exhibit deposition of phosphorylatedTDP-43. Thus, a loss of function ofTMEM106B may enhance the risk forGRN-associatedFTLDby reduced protein turnover in the lysosomal/autophagic system.
AU  - Werner, G.*
AU  - Damme, M.*
AU  - Schludi, M.*
AU  - Gnoerich, J.*
AU  - Wind, K.*
AU  - Fellerer, K.*
AU  - Wefers, B.
AU  - Wurst, W.
AU  - Edbauer, D.*
AU  - Brendel, M.*
AU  - Haass, C.*
AU  - Capell, A.*
C1  - 60194
C2  - 49217
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin-deficient mice.
JO  - EMBO Rep.
VL  - 21
IS  - 10
PB  - Wiley
PY  - 2020
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - How the age-associated decline of immune function leads to increased cancer incidence is poorly understood. Here, we have characterised the cellular composition of the gamma delta T-cell pool in peripheral lymph nodes (pLNs) upon ageing. We find that ageing has minimal cell-intrinsic effects on function and global gene expression of gamma delta T cells, and gamma delta TCR diversity remains stable. However, ageing alters TCR delta chain usage and clonal structure of gamma delta T-cell subsets. Importantly, IL-17-producing gamma delta 17 T cells dominate the gamma delta T-cell pool of aged mice-mainly due to the selective expansion of V gamma 6(+) gamma delta 17 T cells and augmented gamma delta 17 polarisation of V gamma 4(+) T cells. Expansion of the gamma delta 17 T-cell compartment is mediated by increased IL-7 expression in the T-cell zone of old mice. In a Lewis lung cancer model, pro-tumourigenic V gamma 6(+) gamma delta 17 T cells are exclusively activated in the tumour-draining LN and their infiltration into the tumour correlates with increased tumour size in aged mice. Thus, upon ageing, substantial compositional changes in gamma delta T-cell pool in the pLN lead to an unbalanced gamma delta T-cell response in the tumour that is associated with accelerated tumour growth.
AU  - Chen, H.C.*
AU  - Eling, N.*
AU  - Martinez Jimenez, C.P.
AU  - O'Brien, L.M.*
AU  - Carbonaro, V.*
AU  - Marioni, J.C.*
AU  - Odom, D.T.*
AU  - de la Roche, M.*
C1  - 56545
C2  - 47104
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - IL-7-dependent compositional changes within the gamma delta T cell pool in lymph nodes during ageing lead to an unbalanced anti-tumour response.
JO  - EMBO Rep.
VL  - 20
IS  - 8
PB  - Wiley
PY  - 2019
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Aberrant activity of the glucocorticoid (GC)/glucocorticoid receptor (GR) endocrine system has been linked to obesity-related metabolic dysfunction. Traditionally, the GC/GR axis has been believed to play a crucial role in adipose tissue formation and function in both, white (WAT) and brown adipose tissue (BAT). While recent studies have challenged this notion for WAT, the contribution of GC/GR signaling to BAT-dependent energy homeostasis remained unknown. Here, we have generated and characterized a BAT-specific GR-knockout mouse (GR(BATKO)), for the first time allowing to genetically interrogate the metabolic impact of BAT-GR. The HPA axis in GR(BATKO) mice was intact, as was the ability of mice to adapt to cold. BAT-GR was dispensable for the adaptation to fasting-feeding cycles and the development of diet-induced obesity. In obesity, glucose and lipid metabolism, insulin sensitivity, and food intake remained unchanged, aligning with the absence of changes in thermogenic gene expression. Together, we demonstrate that the GR in UCP1-positive BAT adipocytes plays a negligible role in systemic metabolism and BAT function, thereby opposing a long-standing paradigm in the field.
AU  - Glantschnig, C.
AU  - Mattijssen, F.
AU  - Vogl, E.S.
AU  - Ali Khan, A.
AU  - Rios Garcia, M.
AU  - Fischer, K.
AU  - Müller, T.D.
AU  - Uhlenhaut, N.H.
AU  - Nawroth, P.P.
AU  - Scheideler, M.
AU  - Rose, A.J.*
AU  - Pellegata, N.S.
AU  - Herzig, S.
C1  - 56982
C2  - 47389
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - The glucocorticoid receptor in brown adipocytes is dispensable for control of energy homeostasis.
JO  - EMBO Rep.
VL  - 20
IS  - 11
PB  - Wiley
PY  - 2019
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - In most eukaryotes, constitutive heterochromatin is associated with H3K9me3 and HP1 alpha. The latter has been shown to play a role in heterochromatin formation through liquid-liquid phase separation. However, many other proteins are known to regulate and/or interact with constitutive heterochromatic regions in several species. We postulate that some of these heterochromatic proteins may play a role in the regulation of heterochromatin formation by liquid-liquid phase separation. Indeed, an analysis of the constitutive heterochromatin proteome shows that proteins associated with constitutive heterochromatin are significantly more disordered than a random set or a full nucleome set of proteins. Interestingly, their expression begins low and increases during preimplantation development. These observations suggest that the preimplantation embryo is a useful model to address the potential role for phase separation in heterochromatin formation, anticipating exciting research in the years to come.
AU  - Guthmann, M.
AU  - Burton, A.
AU  - Torres-Padilla, M.E.
C1  - 57297
C2  - 47675
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Expression and phase separation potential of heterochromatin proteins during early mouse development.
JO  - EMBO Rep.
VL  - 20
IS  - 12
PB  - Wiley
PY  - 2019
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Members of the GxGD-type intramembrane aspartyl proteases have emerged as key players not only in fundamental cellular processes such as B-cell development or protein glycosylation, but also in development of pathologies, such as Alzheimer's disease or hepatitis virus infections. However, one member of this protease family, signal peptide peptidase-like 2c (SPPL2c), remains orphan and its capability of proteolysis as well as its physiological function is still enigmatic. Here, we demonstrate that SPPL2c is catalytically active and identify a variety of SPPL2c candidate substrates using proteomics. The majority of the SPPL2c candidate substrates cluster to the biological process of vesicular trafficking. Analysis of selected SNARE proteins reveals proteolytic processing by SPPL2c that impairs vesicular transport and causes retention of cargo proteins in the endoplasmic reticulum. As a consequence, the integrity of subcellular compartments, in particular the Golgi, is disturbed. Together with a strikingly high physiological SPPL2c expression in testis, our data suggest involvement of SPPL2c in acrosome formation during spermatogenesis.
AU  - Papadopoulou, A.A.*
AU  - Müller, S.A.*
AU  - Mentrup, T.*
AU  - Shmueli, M.D.*
AU  - Niemeyer, J.*
AU  - Haug-Kröper, M.*
AU  - von Blume, J.*
AU  - Mayerhofer, A.*
AU  - Feederle, R.
AU  - Schröder, B.*
AU  - Lichtenthaler, S.F.*
AU  - Fluhrer, R.*
C1  - 55519
C2  - 46316
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Signal peptide peptidase-like 2c impairs vesicular transport and cleaves SNARE proteins.
JO  - EMBO Rep.
VL  - 20
IS  - 3
PB  - Wiley
PY  - 2019
SN  - 1469-221X
ER  - 

TY  - JOUR
AU  - Papadopoulou, A.A.*
AU  - Müller, S.A.*
AU  - Mentrup, T.*
AU  - Shmueli, M.D.*
AU  - Niemeyer, J.*
AU  - Haug-Kröper, M.*
AU  - von Blume, J.*
AU  - Mayerhofer, A.*
AU  - Feederle, R.
AU  - Schröder, B.*
AU  - Lichtenthaler, S.F.*
AU  - Fluhrer, R.*
C1  - 57806
C2  - 47903
TI  - Signal peptide peptidase-like 2c impairs vesicular transport and cleaves SNARE proteins.
JO  - EMBO Rep.
VL  - 20
IS  - 5
PY  - 2019
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Cachexia is a wasting disorder that accompanies many chronic diseases including cancer and results from an imbalance of energy requirements and energy uptake. In cancer cachexia, tumor-secreted factors and/or tumor-host interactions cause this imbalance, leading to loss of adipose tissue and skeletal and cardiac muscle, which weakens the body. In this review, we discuss how energy enters the body and is utilized by the different organs, including the gut, liver, adipose tissue, and muscle, and how these organs contribute to the energy wasting observed in cachexia. We also discuss futile cycles both between the organs and within the cells, which are often used to fine-tune energy supply under physiologic conditions. Ultimately, understanding the complex interplay of pathologic energy-wasting circuits in cachexia can bring us closer to identifying effective treatment strategies for this devastating wasting disease.
AU  - Rohm, M.
AU  - Zeigerer, A.
AU  - Machado, J.
AU  - Herzig, S.
C1  - 55730
C2  - 46480
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Energy metabolism in cachexia.
JO  - EMBO Rep.
VL  - 20
IS  - 3
PB  - Wiley
PY  - 2019
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Scar formation after brain injury is still poorly understood. To further elucidate such processes, here, we examine the interplay between astrocyte proliferation taking place predominantly at the vascular interface and monocyte invasion. Using genetic mouse models that decrease or increase reactive astrocyte proliferation, we demonstrate inverse effects on monocyte numbers in the injury site. Conversely, reducing monocyte invasion using CCR2 mice causes a strong increase in astrocyte proliferation, demonstrating an intriguing negative cross-regulation between these cell types at the vascular interface. CCR2 mice show reduced scar formation with less extracellular matrix deposition, smaller lesion site and increased neuronal coverage. Surprisingly, the GFAP scar area in these mice is also significantly decreased despite increased astrocyte proliferation. Proteomic analysis at the peak of increased astrocyte proliferation reveals a decrease in extracellular matrix synthesizing enzymes in the injury sites of CCR2 mice, highlighting how early key aspects of scar formation are initiated. Taken together, we provide novel insights into the cross-regulation of juxtavascular proliferating astrocytes and invading monocytes as a crucial mechanism of scar formation upon brain injury.
AU  - Frik, J.
AU  - Merl-Pham, J.
AU  - Plesnila, N.*
AU  - Mattugini, N.
AU  - Kjell, J.
AU  - Kraska, J.*
AU  - Gómez, R.M.*
AU  - Hauck, S.M.
AU  - Sirko, S.
AU  - Götz, M.
C1  - 53379
C2  - 44580
TI  - Cross-talk between monocyte invasion and astrocyte proliferation regulates scarring in brain injury.
JO  - EMBO Rep.
VL  - 19
IS  - 5
PY  - 2018
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Sequence variations in the triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to an increased risk for neurodegenerative disorders such as Alzheimer's disease and frontotemporal lobar degeneration. In the brain, TREM2 is predominantly expressed in microglia. Several disease-associated TREM2 variants result in a loss of function by reducing microglial phagocytosis, impairing lipid sensing, preventing binding of lipoproteins and affecting shielding of amyloid plaques. We here investigate the consequences of TREM2 loss of function on the microglia transcriptome. Among the differentially expressed messenger RNAs in wild-type and Trem2(-/-) microglia, gene clusters are identified which represent gene functions in chemotaxis, migration and mobility. Functional analyses confirm that loss of TREM2 impairs appropriate microglial responses to injury and signals that normally evoke chemotaxis on multiple levels. In an ex vivo organotypic brain slice assay, absence of TREM2 reduces the distance migrated by microglia. Moreover, migration towards defined chemo-attractants is reduced upon ablation of TREM2 and can be rescued by TREM2 re-expression. In vivo, microglia lacking TREM2 migrate less towards injected apoptotic neurons, and outgrowth of microglial processes towards sites of laser-induced focal CNS damage in the somatosensory cortex is slowed. The apparent lack of chemotactic stimulation upon depletion of TREM2 is consistent with a stable expression profile of genes characterizing the homoeostatic signature of microglia.
AU  - Mazaheri, F.*
AU  - Snaidero, N.*
AU  - Kleinberger, G.*
AU  - Madore, C.*
AU  - Daria, A.*
AU  - Werner, G.*
AU  - Krasemann, S.*
AU  - Capell, A.*
AU  - Trümbach, D.
AU  - Wurst, W.
AU  - Brunner, B.*
AU  - Bultmann, S.*
AU  - Tahirovic, S.*
AU  - Kerschensteiner, M.*
AU  - Misgeld, T.*
AU  - Butovsky, O.*
AU  - Haass, C.*
C1  - 51094
C2  - 43087
SP  - 1186-1198
TI  - TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury.
JO  - EMBO Rep.
VL  - 18
IS  - 7
PY  - 2017
SN  - 1469-221X
ER  - 

TY  - JOUR
AU  - Müller, R.*
AU  - Hanson, C.*
AU  - Hanson, M.S.*
AU  - Penkler, M.*
AU  - Samaras, G.*
AU  - Chiapperino, L.*
AU  - Dupré, J.*
AU  - Kenney, M.*
AU  - Kuzawa, C.W.*
AU  - Latimer, J.*
AU  - Lloyd, S.*
AU  - Lunkes, A.
AU  - MacDonald, M.*
AU  - Meloni, M.*
AU  - Nerlich, B.*
AU  - Panese, F.*
AU  - Pickersgill, M.*
AU  - Richardson, S.D.*
AU  - Rüegg, J.*
AU  - Schmitz, S.*
AU  - Stelmach, A.*
AU  - Villa, P.I.*
C1  - 51951
C2  - 43684
CY  - Hoboken
SP  - 1677-1682
TI  - The biosocial genome? Interdisciplinary perspectives on environmental epigenetics, health and society.
JO  - EMBO Rep.
VL  - 18
IS  - 10
PB  - Wiley
PY  - 2017
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Brown adipose tissue (BAT) has received enormous scientific and lay attention in the recent past as its thermogenic, energy‐consuming capacities represent prime candidates for therapeutic interventions toward obesity, glucose intolerance, and diabetes even in humans. The overall positive effects of BAT activation and recruitment on systemic energy homeostasis have been largely attributed to the inherent ability of brown adipocytes to combust fatty acid and glucose energy substrates through mitochondrial uncoupling, driven by the unique expression of uncoupling protein 1 (UCP1). Two recent reports by Boutant et al and Mahdaviani et al now identify the GTPase mitofusin (Mfn) 2 as a key determinant of BAT thermogenic function that is largely independent of its previously described role in mitochondrial fusion [1,2].
AU  - Scheideler, M.
AU  - Herzig, S.
C1  - 51193
C2  - 43114
SP  - 1039-1040
TI  - Let's burn whatever you have: Mitofusin 2 metabolically re-wires brown adipose tissue.
JO  - EMBO Rep.
VL  - 18
PY  - 2017
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Lipopolysaccharide-responsive beige-like anchor protein (LRBA) belongs to the enigmatic class of BEACH domain-containing proteins, which have been attributed various cellular functions, typically involving intracellular protein and membrane transport processes. Here, we show that LRBA deficiency in mice leads to progressive sensorineural hearing loss. In LRBA knockout mice, inner and outer hair cell stereociliary bundles initially develop normally, but then partially degenerate during the second postnatal week. LRBA deficiency is associated with a reduced abundance of radixin and Nherf2, two adaptor proteins, which are important for the mechanical stability of the basal taper region of stereocilia. Our data suggest that due to the loss of structural integrity of the central parts of the hair bundle, the hair cell receptor potential is reduced, resulting in a loss of cochlear sensitivity and functional loss of the fraction of spiral ganglion neurons with low spontaneous firing rates. Clinical data obtained from two human patients with protein-truncating nonsense or frameshift mutations suggest that LRBA deficiency may likewise cause syndromic sensorineural hearing impairment in humans, albeit less severe than in our mouse model.
AU  - Vogl, C.*
AU  - Butola, T.*
AU  - Haag, N.*
AU  - Hausrat, T.J.*
AU  - Leitner, M.G.*
AU  - Moutschen, M.*
AU  - Lefèbvre, P.P.*
AU  - Speckmann, C.*
AU  - Garrett, L.
AU  - Becker, L.
AU  - Fuchs, H.
AU  - Hrabě de Angelis, M.
AU  - Nietzsche, S.*
AU  - Kessels, M.M.*
AU  - Oliver, D.*
AU  - Kneussel, M.*
AU  - Kilimann, M.W.*
AU  - Strenzke, N.*
C1  - 51859
C2  - 43525
CY  - Hoboken
SP  - 2015-2029
TI  - The BEACH protein LRBA is required for hair bundle maintenance in cochlear hair cells and for hearing.
JO  - EMBO Rep.
VL  - 18
IS  - 11
PB  - Wiley
PY  - 2017
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Old age is associated with a progressive decline of mitochondrial function and changes in nuclear chromatin. However, little is known about how metabolic activity and epigenetic modifications change as organisms reach their midlife. Here, we assessed how cellular metabolism and protein acetylation change during early aging in Drosophila melanogaster. Contrary to common assumptions, we find that flies increase oxygen consumption and become less sensitive to histone deacetylase inhibitors as they reach midlife. Further, midlife flies show changes in the metabolome, elevated acetyl-CoA levels, alterations in protein-notably histone-acetylation, as well as associated transcriptome changes. Based on these observations, we decreased the activity of the acetyl-CoA-synthesizing enzyme ATP citrate lyase (ATPCL) or the levels of the histone H4 K12-specific acetyltransferase Chameau. We find that these targeted interventions both alleviate the observed aging-associated changes and promote longevity. Our findings reveal a pathway that couples changes of intermediate metabolism during aging with the chromatin-mediated regulation of transcription and changes in the activity of associated enzymes that modulate organismal life span.
AU  - Peleg, S.*
AU  - Feller, C.*
AU  - Forne, I.*
AU  - Schiller, E.
AU  - Sévin, D.C.*
AU  - Schauer, T.*
AU  - Regnard, C.*
AU  - Straub, T.*
AU  - Prestel, M.*
AU  - Klima, C.*
AU  - Schmitt Nogueira, M.*
AU  - Becker, L.
AU  - Klopstock, T.*
AU  - Sauer, U.*
AU  - Becker, P.B.*
AU  - Imhof, A.*
AU  - Ladurner, A.G.*
C1  - 47710
C2  - 39549
SP  - 455-469
TI  - Life span extension by targeting a link between metabolism and histone acetylation in Drosophila.
JO  - EMBO Rep.
VL  - 17
IS  - 3
PY  - 2016
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - More than 50% of mammalian genomes consist of retrotransposon sequences. Silencing of retrotransposons by heterochromatin is essential to ensure genomic stability and transcriptional integrity. Here, we identified a short sequence element in intracisternal A particle (IAP) retrotransposons that is sufficient to trigger heterochromatin formation. We used this sequence in a genome-wide shRNA screen and identified the chromatin remodeler Atrx as a novel regulator of IAP silencing. Atrx binds to IAP elements and is necessary for efficient heterochromatin formation. In addition, Atrx facilitates a robust and largely inaccessible heterochromatin structure as Atrx knockout cells display increased chromatin accessibility at retrotransposons and non-repetitive heterochromatic loci. In summary, we demonstrate a direct role of Atrx in the establishment and robust maintenance of heterochromatin.
AU  - Sadic, D.*
AU  - Schmidt, K.*
AU  - Groh, S.*
AU  - Kondofersky, I.
AU  - Ellwart, J.W.
AU  - Fuchs, C.
AU  - Theis, F.J.
AU  - Schotta, G.*
C1  - 45038
C2  - 37143
SP  - 836-850
TI  - Atrx promotes heterochromatin formation at retrotransposons.
JO  - EMBO Rep.
VL  - 16
IS  - 7
PY  - 2015
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - In eukaryotes, the molecular chaperones Hsp90 and Hsp70 are connected via the co-chaperone Sti1/Hop, which allows transfer of clients. Here, we show that the basic functions of yeast Sti1 and human Hop are conserved. These include the simultaneous binding of Hsp90 and Hsp70, the inhibition of the ATPase activity of Hsp90, and the ability to support client activation in vivo. Importantly, we reveal that both Hop and Sti1 are subject to inhibitory phosphorylation, although the sites modified and the influence of regulatory phosphorylation is species specific. Phospho-mimetic variants have a reduced ability to activate clients in vivo and different affinity for Hsp70. Hop is more tightly regulated, as phosphorylation affects also the interaction with Hsp90 and induces structural rearrangements in the core part of the protein.
AU  - Röhl, A.*
AU  - Tippel, F.*
AU  - Bender, E.*
AU  - Schmid, A.B.*
AU  - Richter, K.*
AU  - Madl, T.
AU  - Buchner, J.*
C1  - 43047
C2  - 35955
SP  - 240-249
TI  - Hop/Sti1 phosphorylation inhibits its co-chaperone function.
JO  - EMBO Rep.
VL  - 16
IS  - 2
PY  - 2014
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Post-translational histone modifications have essential roles in controlling nuclear processes; however, the specific mechanisms regulating these modifications and their combinatorial activities remain elusive. Cyclin-dependent kinase 9 (CDK9) regulates gene expression by phosphorylating transcriptional regulatory proteins, including the RNA polymerase II carboxy-terminal domain. Here, we show that CDK9 activity is essential for maintaining global and gene-associated levels of histone H2B monoubiquitination (H2Bub1). Furthermore, CDK9 activity and H2Bub1 help to maintain correct replication-dependent histone messenger RNA (mRNA) 3'-end processing. CDK9 knockdown consistently resulted in inefficient recognition of the correct mRNA 3'-end cleavage site and led to increased read-through of RNA polymerase II to an alternative downstream polyadenylation signal. Thus, CDK9 acts to integrate phosphorylation during transcription with chromatin modifications to control co-transcriptional histone mRNA processing.
AU  - Pirngruber, J.*
AU  - Shchebet, A.*
AU  - Morris, A.A.*
AU  - Shema, E.*
AU  - Minsky, N.*
AU  - Chapman, R.D.
AU  - Eick, D.
AU  - Aylon, Y.*
AU  - Oren, M.*
AU  - Johnsen, S.A.*
C1  - 1639
C2  - 26303
SP  - 894-900
TI  - CDK9 directs H2B monoubiquitination and controls replication-dependent histone mRNA 3'-end processing.
JO  - EMBO Rep.
VL  - 10
IS  - 8
PB  - Nature Publ. Group
PY  - 2009
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - The Carma1-Bcl10-Malt1 (CBM) complex connects T-cell receptor (TCR) signalling to the canonical I kappa B kinase (IKK)/NF (nuclear factor)-kappa B pathway. Earlier studies have indicated that the COP9 signalosome (CSN), a pleiotropic regulator of the ubiquitin/26S proteasome system, controls antigen responses in T cells. The CSN is required for the degradation of the NF-kappa B inhibitor I kappa B alpha, but other molecular targets involved in T-cell signalling remained elusive. Here, we identify the CSN subunit 5 (CSN5) as a new interactor of Malt1 and Carma1. T-cell activation triggers the recruitment of the CSN to the CBM complex, and CSN downregulation impairs TCR-induced IKK activation. Furthermore, the CSN is required for maintaining the stability of Bcl10 in response to T-cell activation. Taken together, our data provide evidence for a functional link between the evolutionarily conserved CSN and the adaptive immunoregulatory CBM complex in T cells.
AU  - Welteke, V.
AU  - Eitelhuber, A.C.
AU  - Düwel, M.
AU  - Schweitzer, K.*
AU  - Naumann, M.*
AU  - Krappmann, D.
C1  - 1682
C2  - 26161
SP  - 642-648
TI  - COP9 signalosome controls the Carma1-Bcl10-Malt1 complex upon T-cell stimulation.
JO  - EMBO Rep.
VL  - 10
IS  - 6
PB  - Nature Publ. Group
PY  - 2009
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Cytoplasmic localization and localized translation of messenger RNAs contribute to asymmetrical protein distribution. Recognition of localized mRNAs by RNA-binding proteins can occur in the cytoplasm or, alternatively, co- or post-transcriptionally in the nucleus. In budding yeast, mRNAs destined for localization are bound by the She2 protein before their nuclear export. Here, we show that a specific transcript, known as ASH1 mRNA, and She2 localize specifically to the nucleolus when their nuclear export is blocked. Nucleolar She2 localization is enhanced in a She2 mutant that cannot bind to RNA. A fusion protein of the amino terminus of She3 and She2 (She3N-She2) fails to enter the nucleus, but does not impair ASH1 mRNA localization. Instead, these cells fail to distribute Ash1 protein asymmetrically, which is caused by a defective translational control of ASH1 mRNA. Our results indicate that the nucleolar transit of RNA-binding proteins such as She2 is necessary for the correct assembly of translationally silenced localizing messenger ribonucleoproteins.
AU  - Du, T.G.*
AU  - Jellbauer, S.*
AU  - Müller, M.
AU  - Schmid, M.*
AU  - Niessing, D.
AU  - Jansen, R.P.*
C1  - 912
C2  - 25431
SP  - 781-787
TI  - Nuclear transit of the RNA-binding protein She2 is required for translational control of localized ASH1 mRNA.
JO  - EMBO Rep.
VL  - 9
IS  - 8
PB  - Nature Publ. Group
PY  - 2008
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - The ubiquitin-like SUMO system functions by a cyclic process of modification and demodification, and recent data suggest that the nucleolus is a site of sumoylation-desumoylation cycles. For example, the tumour suppressor ARF stimulates sumoylation of nucleolar proteins. Here, we show that the nucleolar SUMO-specific protease SENP3 is associated with nucleophosmin (NPM1), a crucial factor in ribosome biogenesis. SENP3 catalyses desumoylation of NPM1-SUMO2 conjugates in vitro and counteracts ARF-induced modification of NPM1 by SUMO2 in vivo. Intriguingly, depletion of SENP3 by short interfering RNA interferes with nucleolar ribosomal RNA processing and inhibits the conversion of the 32S rRNA species to the 28S form, thus phenocopying the processing defect observed on depletion of NPM1. Moreover, mimicking constitutive modification of NPM1 by SUMO2 interferes with 28S rRNA maturation. These results define SENP3 as an essential factor for ribosome biogenesis and suggest that deconjugation of SUMO2 from NPM1 by SENP3 is critically involved in 28S rRNA maturation.
AU  - Haindl, M.*
AU  - Harasim, T.
AU  - Eick, D.
AU  - Müller, S.*
C1  - 2589
C2  - 25743
SP  - 273-279
TI  - The nucleolar SUMO-specific protease SENP3 reverses SUMO modification of nucleophosmin and is required for rRNA processing.
JO  - EMBO Rep.
VL  - 9
IS  - 3
PB  - Nature Publ. Group
PY  - 2008
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Cleavage of the amyloid precursor protein (APP) is a crucial event in Alzheimer disease pathogenesis that creates the amyloid-beta peptide (A beta) and liberates the carboxy-terminal APP intracellular domain (AICD) into the cytosol. The interaction of the APP C terminus with the adaptor protein Fe65 mediates APP trafficking and signalling, and is thought to regulate APP processing and A beta generation. We determined the crystal structure of the AICD in complex with the C-terminal phospho-tyrosine-binding (PTB) domain of Fe65. The unique interface involves the NPxY PTB-binding motif and two alpha helices. The amino-terminal helix of the AICD is capped by threonine T-668, an Alzheimer disease-relevant phosphorylation site involved in Fe65-binding regulation. The structure together with mutational studies, isothermal titration calorimetry and nuclear magnetic resonance experiments sets the stage for unterstanding T-668 phosphorylation-dependent complex regulation at a molecular level. A molecular switch model is proposed.
AU  - Radzimanowski, J.*
AU  - Simon, B.*
AU  - Sattler, M.
AU  - Beyreuther, K.*
AU  - Sinning, I.*
AU  - Wild, K.*
C1  - 4884
C2  - 25942
SP  - 1134-1140
TI  - Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2.
JO  - EMBO Rep.
VL  - 9
IS  - 11
PB  - Nature Publ. Group
PY  - 2008
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - The crucial role of individual Notch receptors and the mechanism by which they maintain intestinal crypt progenitor cells were assessed by using a series of inducible gut-specific Notch mutant mice. We found that Notch1 and Notch2 receptors function redundantly in the gut, as only simultaneous loss of both receptors results in complete conversion of proliferating crypt progenitors into post-mitotic goblet cells. This conversion correlates with the loss of Hes1 expression and derepression of the cyclin-dependent kinase (CDK) inhibitors p27Kip1 and p57Kip2. We also found that the promoter of both CDK inhibitor genes is occupied by the Notch effector Hes1 in wild-type crypt progenitor cells. Thus, our results indicate that Notch-mediated Hes1 expression contributes to the maintenance of the proliferative crypt compartment of the small intestine by transcriptionally repressing two CDK inhibitors.
AU  - Riccio, O.*
AU  - van Gijn, M.E.*
AU  - Bezdek, A.C.*
AU  - Pellegrinet, L.*
AU  - van Es, J.H.*
AU  - Zimber-Strobl, U.
AU  - Strobl, L.J.
AU  - Honjo, T.*
AU  - Clevers, H.*
AU  - Radtke, F.*
C1  - 463
C2  - 25457
SP  - 377-383
TI  - Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2.
JO  - EMBO Rep.
VL  - 9
IS  - 4
PB  - Nature Publ. Group
PY  - 2008
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Members of the Argonaute (Ago) protein family associate with small RNAs and have important roles in RNA silencing. Here, we analysed Ago1- and Ago2-containing protein complexes in human cells. Separation of Ago-associated messenger ribonucleoproteins (mRNPs) showed that Ago1 and Ago2 reside in three complexes with distinct Dicer and RNA-induced silencing complex activities. A comprehensive proteomic analysis of Ago-containing mRNPs identified a large number of proteins involved in RNA metabolism. By using co-immunoprecipitation experiments followed by RNase treatment, we biochemically mapped interactions within Ago mRNPs. Using reporter assays and knockdown experiments, we showed that the putative RNA-binding protein RBM4 is required for microRNA-guided gene regulation.
AU  - Höck, J.*
AU  - Weinmann, L.*
AU  - Ender, C.*
AU  - Rüdel, S.*
AU  - Kremmer, E.
AU  - Raabe, M.*
AU  - Urlaub, H.*
AU  - Meister, G.*
C1  - 2348
C2  - 24806
SP  - 1052-1060
TI  - Proteomic and functional analysis of Argonaute-containing mRNA-protein complexes in human cells.
JO  - EMBO Rep.
VL  - 8
IS  - 11
PB  - Nature Publ. Group
PY  - 2007
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - The exosome is a protein complex that is important in both degradation and 3'-processing of eukaryotic RNAs. We present the crystal structure of the Rrp40 exosome subunit from Saccharomyces cerevisiae at a resolution of 2.2 A. The structure comprises an S1 domain and an unusual KH (K homology) domain. Close packing of the S1 and KH domains is stabilized by a GxNG sequence, which is uniquely conserved in exosome KH domains. Nuclear magnetic resonance data reveal the presence of a manganese-binding site at the interface of the two domains. Isothermal titration calorimetry shows that Rrp40 and archaeal Rrp4 alone have very low intrinsic affinity for RNA. The affinity of an archaeal core exosome for RNA is significantly increased in the presence of the S1-KH subunit Rrp4, indicating that multiple subunits might contribute to cooperative binding of RNA substrates by the exosome.
AU  - Oddone, A.*
AU  - Lorentzen, E.*
AU  - Basquin, J.*
AU  - Gasch, A.*
AU  - Rybin, V.*
AU  - Conti, E.*
AU  - Sattler, M.
C1  - 3537
C2  - 24823
SP  - 63-69
TI  - Structural and biochemical characterization of the yeast exosome component Rrp40.
JO  - EMBO Rep.
VL  - 8
IS  - 1
PB  - Nature Publ. Group
PY  - 2007
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Proteins bearing an endoplasmic reticulum (ER) leader are inserted into the ER followed by cleavage of the signal peptide. Major histocompatibility complex class I-restricted T-cell epitopes can be generated from these proteins by the proteasome after retrotranslocation into the cytosol. Here, we show that an HLA-A*0201-restricted epitope from prostate stem cell antigen contains the cleavage site of the ER signal peptidase. The resulting cleavage products fail to bind to HLA-A*0201 and are not recognized by T lymphocytes. As processing of prostate stem cell antigen by signal peptidase occurs immediately after co-translational insertion, the epitope must be processed from polypeptides that have never reached the ER. The processing of this epitope depends on the proteasome and the transporter associated with antigen processing and shows a novel pathway of class I processing that relies on the failure of ER-targeted proteins to reach their target compartment.
AU  - Schlosser, E.*
AU  - Otero, C.*
AU  - Wuensch, C.*
AU  - Kessler, B.*
AU  - Edelmann, M.*
AU  - Brunisholz, R.*
AU  - Drexler, I.
AU  - Legler, D.F.*
AU  - Groettrup, M.
C1  - 1792
C2  - 24713
SP  - 945-951
TI  - A novel cytosolic class I antigen-processing pathway for endoplasmic-reticulum-targeted proteins.
JO  - EMBO Rep.
VL  - 8
IS  - 10
PB  - Nature Publ. Group
PY  - 2007
SN  - 1469-221X
ER  - 

TY  - JOUR
AB  - Inhibition of amyloid β‐peptide (Aβ) production by blocking γ‐secretase activity is at present one of the most promising therapeutic strategies to slow progression of Alzheimer's disease pathology. γ‐secretase inhibitors apparently block Aβ generation via interference with presenilin (PS) function. Besides being an essential component of the γ‐secretase complex, PS itself may be an aspartyl protease with γ‐secretase activity, which is not only required for Aβ production but also for a similar proteolytic process involved in Notch signaling. Here we demonstrate that treatment of zebrafish embryos with a known γ‐secretase inhibitor affects embryonic development in a manner indistinguishable from Notch signaling deficiencies at morphological, molecular and biochemical levels. This indicates severe side‐effects of γ‐secretase inhibitors in any Notch‐dependent cell fate decision and demonstrates that the zebrafish is an ideal vertebrate system to validate compounds that selectively affect Aβ production, but not Notch signaling, under in vivo conditions.
AU  - Geling, A.*
AU  - Steiner, H.*
AU  - Willem, M.*
AU  - Bally-Cuif, L.
AU  - Haas, C.*
C1  - 22103
C2  - 20769
SP  - 688-694
TI  - A gamma-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish.
JO  - EMBO Rep.
VL  - 3
IS  - 7
PY  - 2002
SN  - 1469-221X
ER  -