title: Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production.
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.
authors.affiliation: 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.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: White
authors.affiliation: 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.
authors.forename: Kate
authors.initials: K
authors.lastname: McArthur
authors.affiliation: 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.
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.affiliation: ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
authors.forename: Rachael M
authors.initials: RM
authors.lastname: Lane
authors.affiliation: Integrated Department of Immunology, University of Colorado Denver School of Medicine and National Jewish Health, Denver, CO 80206, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Cambier
authors.affiliation: 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.
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Herold
authors.affiliation: 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.
authors.forename: Mark F
authors.initials: MF
authors.lastname: van Delft
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, Parkville 3010, Australia.
authors.forename: Sammy
authors.initials: S
authors.lastname: Bedoui
authors.affiliation: 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.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lessene
authors.affiliation: 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.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Ritchie
authors.affiliation: 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.
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kile
mesh_terms: D000818:Animals; D017209:Apoptosis; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000145:classification / Q000378:metabolism*; D003433:Crosses, Genetic; D004272:DNA, Mitochondrial / Q000378:metabolism; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D000099197:STING Protein
chemical_list: D053453:Caspase 9; D020169:Caspases; D004272:DNA, Mitochondrial; D007370:Interferon Type I; D008565:Membrane Proteins; C530855:Sting1 protein, mouse; D000099197:STING Protein