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Titel:

Reduced mitochondrial resilience enables non-canonical induction of apoptosis after TNF receptor signaling in virus-infected hepatocytes.

Dokumenttyp:
Journal Article
Autor(en):
Lampl, Sandra; Janas, Marianne K; Donakonda, Sainitin; Brugger, Marcus; Lohr, Kerstin; Schneider, Annika; Manske, Katrin; Sperl, Laura E; Wettmarshausen, Jennifer; Müller, Constanze; Laschinger, Melanie; Hartmann, Daniel; Hüser, Norber; Perrochi, Fabiana; Schmitt-Kopplin, Philippe; Hagn, Franz; Zender, Lars; Hornung, Veit; Borner, Christoph; Pichlmair, Andreas; Kashkar, Hamid; Klingenspor, Martin; Prinz, Marco; Schreiner, Sabrina; Conrad, Marcus; Jost, Philipp J; Zischka, Hans; Steiger, Katja; K...     »
Abstract:
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.
Zeitschriftentitel:
J Hepatol
Jahr:
2020
Band / Volume:
73
Heft / Issue:
6
Seitenangaben Beitrag:
1347-1359
Volltext / DOI:
doi:10.1016/j.jhep.2020.06.026
PubMed:
http://view.ncbi.nlm.nih.gov/pubmed/32598967
Print-ISSN:
0168-8278
TUM Einrichtung:
Chirurgische Klinik und Poliklinik; III. Medizinische Klinik und Poliklinik (Hämatologie / Onkologie); Institut für Allgemeine Pathologie und Pathologische Anatomie; Institut für Experimentelle Onkologie und Therapieforschung; Institut für Toxikologie und Umwelthygiene; Institut für Virologie ; Roman Herzog Comprehensive Cancer Center
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