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Lampl, S.* ; Janas, M.K.* ; Donakonda, S.* ; Brugger, M.* ; Lohr, K.* ; Schneider, A.* ; Manske, K.* ; Sperl, L.E. ; 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, P.J.* ; Zischka, H. ; Steiger, K.* ; Krönke, M.* ; Zehn, D.* ; Protzer, U. ; Heikenwälder, M.* ; Knolle, P.A.* ; Wohlleber, D.*

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

J. Hepatol. 73, 1347-1359 (2020)
DOI Order publishers version
Open Access Green: Postprint online available 11/2021
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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Publication type Article: Journal article
Document type Scientific Article
Keywords 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
Quellenangaben Volume: 73, Issue: 6, Pages: 1347-1359 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Radarweg 29, 1043 Nx Amsterdam, Netherlands
Reviewing status Peer reviewed
Grants Bert L & N Kuggie Vallee Foundation
Munich Center for Systems Neurology
DZIF Munich
ERC
EU
Helmholtz Zentrum Munchen
Helmholtz Society
DFG