Reduced mitochondrial resilience enables non-canonical induction of apoptosis after TNF receptor signaling in virus-infected hepatocytes
2020
Abstract Background & Aims Selective elimination of virus-infected hepatocytes occurs through virus-specific CD8 T-cells recognizing peptide-loaded MHC molecules. Here, 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 independent from local inflammation and activation of immune sensory receptors. TNF receptor I was equally relevant for NFkB 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 a so far unknown non-canonical cell-intrinsic pathway promoting apoptosis in hepatocytes. We identified a unique state of mitochondrial vulnerability in virus-infected hepatocytes as 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 towards calcium challenge. In the presence of unchanged TNF induced signaling, ROS-mediated calcium release from the ER 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 cell defense mechanism to selectively eliminate virus-infected hepatocytes by mitochondrial permeability transition.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
46
References
4
Citations
NaN
KQI