Journal
CELL
Volume 159, Issue 7, Pages 1563-1577Publisher
CELL PRESS
DOI: 10.1016/j.cell.2014.11.037
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Funding
- NIAID [AI082030]
- DOD [W81XWH-11-1-0745]
- Blavatnik Family Foundation [M157176]
- NIH [R01-AI093967, R01-AG047632]
- Cancer Prevention and Research Institute of Texas [RP120718-P3]
- United Mitochondrial Disease Foundation
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- American Cancer Society [PF-13-035-01-DMC]
- Grants-in-Aid for Scientific Research [22114007, 14F04416] Funding Source: KAKEN
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The mechanism by which cells undergo death determines whether dying cells trigger inflammatory responses or remain immunologically silent. Mitochondria play a central role in the induction of cell death, as well as in immune signaling pathways. Here, we identify a mechanism by which mitochondria and downstream proapoptotic caspases regulate the activation of antiviral immunity. In the absence of active caspases, mitochondrial outer membrane permeabilization by Bax and Bak results in the expression of type I interferons (IFNs). This induction is mediated by mitochondrial DNA-dependent activation of the cGAS/STING pathway and results in the establishment of a potent state of viral resistance. Our results show that mitochondria have the capacity to simultaneously expose a cell-intrinsic inducer of the IFN response and to inactivate this response in a caspase-dependent manner. This mechanism provides a dual control, which determines whether mitochondria initiate an immunologically silent or a proinflammatory type of cell death.
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