Apoptotic Caspases Suppress Type I Interferon Production via the Cleavage of cGAS, MAVS, and IRF3

• Published in: Molecular cell Vol. 74; no. 1; pp. 19 - 31.e7
• Main Authors: Ning, Xiaohan, Wang, Yutao, Jing, Miao, Sha, Mengyin, Lv, Mengze, Gao, Pengfei, Zhang, Rui, Huang, Xiaojun, Feng, Ji-Ming, Jiang, Zhengfan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.04.2019
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Apoptosis; apoptotic caspase; Caspase 2 - genetics; Caspase 2 - metabolism; Caspase 3 - genetics; Caspase 3 - metabolism; Caspase 7 - genetics; Caspase 7 - metabolism; Caspase 9 - genetics; Caspase 9 - metabolism; caspase-3; caspase-7; Caspases - genetics; Caspases - metabolism; cGAS; cleavage; cytokines; DNA; encephalitis; Female; HEK293 Cells; HeLa Cells; homeostasis; Host-Pathogen Interactions; Humans; Immunity, Innate; immunologically silent; inflammasomes; innate immunity; Interferon Regulatory Factor-3 - genetics; Interferon Regulatory Factor-3 - metabolism; Interferon Type I - metabolism; interferons; IRF3; Male; MAVS; mice; Mice, Inbred C57BL; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; RNA; Sendai virus - immunology; Sendai virus - pathogenicity; Signal Transduction; THP-1 Cells; type I-interferon; Vaccinia virus - immunology; Vaccinia virus - pathogenicity; Virus Diseases - enzymology; Virus Diseases - genetics; Virus Diseases - immunology; Virus Diseases - virology; virus infection; type I-interferon; cleavage; MAVS; innate immunity; IRF3; apoptotic caspase; cGAS; apoptosis; immunologically silent; virus infection
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2019.02.013

Viral infection triggers host defenses through pattern-recognition receptor-mediated cytokine production, inflammasome activation, and apoptosis of the infected cells. Inflammasome-activated caspases are known to cleave cyclic GMP-AMP synthase (cGAS). Here, we found that apoptotic caspases are critically involved in regulating both DNA and RNA virus-triggered host defenses, in which activated caspase-3 cleaved cGAS, MAVS, and IRF3 to prevent cytokine overproduction. Caspase-3 was exclusively required in human cells, whereas caspase-7 was involved only in murine cells to inactivate cGAS, reflecting distinct regulatory mechanisms in different species. Caspase-mediated cGAS cleavage was enhanced in the presence of dsDNA. Alternative MAVS cleavage sites were used to ensure the inactivation of this critical protein. Elevated type I IFNs were detected in caspase-3-deficient cells without any infection. Casp3−/− mice consistently showed increased resistance to viral infection and experimental autoimmune encephalomyelitis. Our results demonstrate that apoptotic caspases control innate immunity and maintain immune homeostasis against viral infection. [Display omitted] •Deficiency in apoptotic caspases leads to elevated IFN production by virus infection•Caspase-3 cleaves cGAS, MAVS, and IRF3 to keep apoptosis immunologically silent•Caspase-7 is differently involved in mouse and human cells to cleave cGAS and MAVS•MAVS is cleaved at alternative sites to ensure caspase-mediated negative regulation Ning et al. find that caspase-3 cleaves and inactivates cGAS, MAVS, and IRF3 to suppress cytokine and type I IFN production. Their findings reveal a role for apoptotic caspases in controlling antiviral innate immunity and keeping apoptosis immunologically silent.