Apoptotic caspases prevent the induction of type i interferons by mitochondrial DNA

Anthony Rongvaux, Ruaidhrí Jackson, Christian C D Harman, Tuo Li, A. Phillip West, Marcel R. De Zoete, Youtong Wu, Brian Yordy, Saquib A. Lakhani, Chia Yi Kuan, Tadatsugu Taniguchi, Gerald S. Shadel, Zhijian J. Chen, Akiko Iwasaki, Richard A. Flavell

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278 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1563-1577
Number of pages15
JournalCell
Volume159
Issue number7
DOIs
StatePublished - Dec 18 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Rongvaux, A., Jackson, R., Harman, C. C. D., Li, T., West, A. P., De Zoete, M. R., Wu, Y., Yordy, B., Lakhani, S. A., Kuan, C. Y., Taniguchi, T., Shadel, G. S., Chen, Z. J., Iwasaki, A., & Flavell, R. A. (2014). Apoptotic caspases prevent the induction of type i interferons by mitochondrial DNA. Cell, 159(7), 1563-1577. https://doi.org/10.1016/j.cell.2014.11.037