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Reduced mitochondrial resilience enables non-canonical induction of apoptosis after TNF receptor signaling in virus-infected hepatocytes.
J. Hepatol. 73, 1347-1359 (2020)
Background & Aims: Selective elimination of virus-infected hepatocytes occurs through virus-specific CD8 T cells recognizing peptide-loaded MHC molecules. Herein, we report that virus-infected hepatocytes are also selectively eliminated through a cell-autonomous mechanism. Methods: We generated recombinant adenoviruses and genetically modified mouse models to identify the molecular mechanisms determining TNF-induced hepatocyte apoptosis in vivo and used in vivo bioluminescence imaging, immunohistochemistry, immunoblot analysis, RNAseq/proteome/phosphoproteome analyses, bioinformatic analyses, mitochondrial function tests. Results: We found that TNF precisely eliminated only virus-infected hepatocytes independently of local inflammation and activation of immune sensory receptors. TNF receptor I was equally relevant for NF-kB activation in healthy and infected hepatocytes, but selectively mediated apoptosis in infected hepatocytes. Caspase 8 activation downstream of TNF receptor signaling was dispensable for apoptosis in virus-infected hepatocytes, indicating an unknown non-canonical cell-intrinsic pathway promoting apoptosis in hepatocytes. We identified a unique state of mitochondrial vulnerability in virus-infected hepatocytes as the cause for this non-canonical induction of apoptosis through TNF. Mitochondria from virus-infected hepatocytes showed normal biophysical and bioenergetic functions but were characterized by reduced resilience to calcium challenge. In the presence of unchanged TNF-induced signaling, reactive oxygen species-mediated calcium release from the endoplasmic reticulum caused mitochondrial permeability transition and apoptosis, which identified a link between extrinsic death receptor signaling and cell-intrinsic mitochondrial-mediated caspase activation. Conclusion: Our findings reveal a novel concept in immune surveillance by identifying a cell-autonomous defense mechanism that selectively eliminates virus-infected hepatocytes through mitochondrial permeability transition. Lay summary: The liver is known for its unique immune functions. Herein, we identify a novel mechanism by which virus-infected hepatocytes can selectively eliminate themselves through reduced mitochondrial resilience to calcium challenge.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Antiviral Immunity ; Hepatocyte Apoptosis ; Mitochondrial Function ; Mitochondrial Permeability Transition ; Tnf; Cd8(+) T-cells; Permeability Transition; Stress-response; Activation; Phosphorylation; Necrosis; Calcium; Protein; Death; Regulators
ISSN (print) / ISBN
0168-8278
e-ISSN
1600-0641
Zeitschrift
Journal of Hepatology
Quellenangaben
Band: 73,
Heft: 6,
Seiten: 1347-1359
Verlag
Elsevier
Verlagsort
Radarweg 29, 1043 Nx Amsterdam, Netherlands
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Structural Biology (STB)
Institute of Diabetes and Obesity (IDO)
Research Unit Analytical BioGeoChemistry (BGC)
Institute of Virology (VIRO)
Institute of Metabolism and Cell Death (MCD)
Institute of Molecular Toxicology and Pharmacology (TOXI)
Institute of Diabetes and Obesity (IDO)
Research Unit Analytical BioGeoChemistry (BGC)
Institute of Virology (VIRO)
Institute of Metabolism and Cell Death (MCD)
Institute of Molecular Toxicology and Pharmacology (TOXI)
Förderungen
Bert L & N Kuggie Vallee Foundation
Munich Center for Systems Neurology
DZIF Munich
ERC
EU
Helmholtz Zentrum Munchen
Helmholtz Society
DFG
Munich Center for Systems Neurology
DZIF Munich
ERC
EU
Helmholtz Zentrum Munchen
Helmholtz Society
DFG