Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Lampl, S; Janas, MK; Donakonda, S; Brugger, M; Lohr, K; Schneider, A; Manske, K; Sperl, LE; Kläger, S; Küster, B; Wettmarshausen, J; Müller, C; Laschinger, M; Hartmann, D; Hüser, N; Perocchi, F; Schmitt-Kopplin, P; Hagn, F; Zender, L; Hornung, V; Borner, C; Pichlmair, A; Kashkar, H; Klingenspor, M; Prinz, M; Schreiner, S; Conrad, M; Jost, PJ; Zischka, H; Steiger, K; Krönke, M; Zehn, D; Protzer, U; Heikenwälder, M; Knolle, PA; Wohlleber, D.
Reduced mitochondrial resilience enables non-canonical induction of apoptosis after TNF receptor signaling in virus-infected hepatocytes.
J Hepatol. 2020; 73(6):1347-1359
Doi: 10.1016/j.jhep.2020.06.026
Web of Science
PubMed
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- Co-Autor*innen der Med Uni Graz
- Jost Philipp
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- Abstract:
- 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. 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. 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. 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. 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. Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
- Find related publications in this database (Keywords)
- TNF
- Hepatocyte apoptosis
- Mitochondrial function
- Mitochondrial permeability transition
- Antiviral immunity