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Cell. 2014 Dec 18;159(7):1549-62. doi: 10.1016/j.cell.2014.11.036.

Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production.

Author information

1
ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia. Electronic address: mwhite@wehi.edu.au.
2
ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
3
Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
4
ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
5
Integrated Department of Immunology, University of Colorado Denver School of Medicine and National Jewish Health, Denver, CO 80206, USA.
6
Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
7
Department of Microbiology and Immunology, The University of Melbourne, Parkville 3010, Australia.
8
ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia; Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville 3010, Australia.
9
Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia; Department of Mathematics and Statistics, The University of Melbourne, Parkville 3010, Australia.
10
ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia. Electronic address: kile@wehi.edu.au.

Abstract

Activated caspases are a hallmark of apoptosis induced by the intrinsic pathway, but they are dispensable for cell death and the apoptotic clearance of cells in vivo. This has led to the suggestion that caspases are activated not just to kill but to prevent dying cells from triggering a host immune response. Here, we show that the caspase cascade suppresses type I interferon (IFN) production by cells undergoing Bak/Bax-mediated apoptosis. Bak and Bax trigger the release of mitochondrial DNA. This is recognized by the cGAS/STING-dependent DNA sensing pathway, which initiates IFN production. Activated caspases attenuate this response. Pharmacological caspase inhibition or genetic deletion of caspase-9, Apaf-1, or caspase-3/7 causes dying cells to secrete IFN-β. In vivo, this precipitates an elevation in IFN-β levels and consequent hematopoietic stem cell dysfunction, which is corrected by loss of Bak and Bax. Thus, the apoptotic caspase cascade functions to render mitochondrial apoptosis immunologically silent.

PMID:
25525874
PMCID:
PMC4520319
DOI:
10.1016/j.cell.2014.11.036
[Indexed for MEDLINE]
Free PMC Article

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