title: Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA.
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.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Rongvaux
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Ruaidhrí
authors.initials: R
authors.lastname: Jackson
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Christian C D
authors.initials: CC
authors.lastname: Harman
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Tuo
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: A Phillip
authors.initials: AP
authors.lastname: West
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute.
authors.forename: Marcel R
authors.initials: MR
authors.lastname: de Zoete
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Youtong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Yordy
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Saquib A
authors.initials: SA
authors.lastname: Lakhani
authors.affiliation: Department of Pediatrics, Division of Neurology and The Center for Neurodegenerative Diseases (CND), Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Kuan
authors.affiliation: Department of Molecular Immunology, Institute of Industrial Science, The University of Tokyo, Tokyo 153-8505, Japan.
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Taniguchi
authors.affiliation: 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.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Shadel
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute.
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute.
authors.forename: Akiko
authors.initials: A
authors.lastname: Iwasaki
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute. Electronic address: richard.flavell@yale.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D014777:Virus Diseases / Q000276:immunology
chemical_list: D004272:DNA, Mitochondrial; D007370:Interferon Type I; D020169:Caspases