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Cell. 2014 Dec 18;159(7):1563-77. doi: 10.1016/j.cell.2014.11.037.

Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA.

Author information

1
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
2
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
4
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute.
5
Department of Pediatrics, Division of Neurology and The Center for Neurodegenerative Diseases (CND), Emory University School of Medicine, Atlanta, GA 30322, USA.
6
Department of Molecular Immunology, Institute of Industrial Science, The University of Tokyo, Tokyo 153-8505, Japan.
7
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA; Departments of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
8
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute.
9
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute. Electronic address: richard.flavell@yale.edu.

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.

PMID:
25525875
PMCID:
PMC4272443
DOI:
10.1016/j.cell.2014.11.037
[Indexed for MEDLINE]
Free PMC Article

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