Lampl, Sandra, Janas, Marianne K., Donakonda, Sainitin ORCID: 0000-0003-3216-8759, Brugger, Marcus, Lohr, Kerstin, Schneider, Annika, Manske, Katrin, Sperl, Laura E., Klaeger, Susan, Kuester, Bernhard, Wettmarshausen, Jennifer, Mueller, Constanze, Laschinger, Melanie, Hartmann, Daniel, Hueser, Norber, Perocchi, Fabiana, Schmitt-Kopplin, Philippe ORCID: 0000-0003-0824-2664, Hagn, Franz, Zender, Lars, Hornung, Veit, Borner, Christoph, Pichlmair, Andreas, Kashkar, Hamid, Klingenspor, Martin, Prinz, Marco, Schreiner, Sabrina, Conrad, Marcus ORCID: 0000-0003-1140-5612, Jost, Philipp J., Zischka, Hans, Steiger, Katja, Kroenke, Martin, Zehn, Dietmar, Protzer, Ulrike, Heikenwaelder, Mathias, Knolle, Percy A. and Wohlleber, Dirk ORCID: 0000-0003-3861-5150 (2020). Reduced mitochondrial resilience enables non-canonical induction of apoptosis after TNF receptor signaling in virus-infected hepatocytes. J. Hepatol., 73 (6). S. 1347 - 1360. AMSTERDAM: ELSEVIER. ISSN 1600-0641

Full text not available from this repository.

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. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lampl, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Janas, Marianne K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Donakonda, SainitinUNSPECIFIEDorcid.org/0000-0003-3216-8759UNSPECIFIED
Brugger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lohr, KerstinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, AnnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Manske, KatrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sperl, Laura E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klaeger, SusanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuester, BernhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wettmarshausen, JenniferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, ConstanzeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laschinger, MelanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartmann, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hueser, NorberUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perocchi, FabianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt-Kopplin, PhilippeUNSPECIFIEDorcid.org/0000-0003-0824-2664UNSPECIFIED
Hagn, FranzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zender, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hornung, VeitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borner, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pichlmair, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kashkar, HamidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klingenspor, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prinz, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schreiner, SabrinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Conrad, MarcusUNSPECIFIEDorcid.org/0000-0003-1140-5612UNSPECIFIED
Jost, Philipp J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zischka, HansUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steiger, KatjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kroenke, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zehn, DietmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Protzer, UlrikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heikenwaelder, MathiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knolle, Percy A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wohlleber, DirkUNSPECIFIEDorcid.org/0000-0003-3861-5150UNSPECIFIED
URN: urn:nbn:de:hbz:38-310413
DOI: 10.1016/j.jhep.2020.06.026
Journal or Publication Title: J. Hepatol.
Volume: 73
Number: 6
Page Range: S. 1347 - 1360
Date: 2020
Publisher: ELSEVIER
Place of Publication: AMSTERDAM
ISSN: 1600-0641
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CD8(+) T-CELLS; PERMEABILITY TRANSITION; STRESS-RESPONSE; ACTIVATION; PHOSPHORYLATION; NECROSIS; CALCIUM; PROTEIN; DEATH; REGULATORSMultiple languages
Gastroenterology & HepatologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/31041

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item