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

Molecular cell, 2019-04, Vol.74 (1), p.19-31.e7 [Peer Reviewed Journal]

2019 Elsevier Inc. ;Copyright © 2019 Elsevier Inc. All rights reserved. ;ISSN: 1097-2765 ;EISSN: 1097-4164 ;DOI: 10.1016/j.molcel.2019.02.013 ;PMID: 30878284

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Title:
Apoptotic Caspases Suppress Type I Interferon Production via the Cleavage of cGAS, MAVS, and IRF3
Author: Ning, Xiaohan ; Wang, Yutao ; Jing, Miao ; Sha, Mengyin ; Lv, Mengze ; Gao, Pengfei ; Zhang, Rui ; Huang, Xiaojun ; Feng, Ji-Ming ; Jiang, Zhengfan
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 ; Caspases - genetics ; Caspases - metabolism ; cGAS ; cleavage ; Female ; HEK293 Cells ; HeLa Cells ; Host-Pathogen Interactions ; Humans ; Immunity, Innate ; immunologically silent ; innate immunity ; Interferon Regulatory Factor-3 - genetics ; Interferon Regulatory Factor-3 - metabolism ; Interferon Type I - metabolism ; IRF3 ; Male ; MAVS ; Mice, Inbred C57BL ; Nucleotidyltransferases - genetics ; Nucleotidyltransferases - metabolism ; 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
Is Part Of: Molecular cell, 2019-04, Vol.74 (1), p.19-31.e7
Description: 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.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 1097-2765
EISSN: 1097-4164
DOI: 10.1016/j.molcel.2019.02.013
PMID: 30878284
Source: Cell Press Free Archives
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Apoptotic Caspases Suppress Type I Interferon Production via the Cleavage of cGAS, MAVS, and IRF3

2019 Elsevier Inc. ;Copyright © 2019 Elsevier Inc. All rights reserved. ;ISSN: 1097-2765 ;EISSN: 1097-4164 ;DOI: 10.1016/j.molcel.2019.02.013 ;PMID: 30878284

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