Apoptotic Caspases Suppress Type I Interferon Production via the Cleavage of cGAS, MAVS, and IRF3.
Mol Cell
; 74(1): 19-31.e7, 2019 04 04.
Article
en En
| MEDLINE
| ID: mdl-30878284
ABSTRACT
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Virosis
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Interferón Tipo I
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Apoptosis
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Caspasas
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Proteínas Adaptadoras Transductoras de Señales
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Factor 3 Regulador del Interferón
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Nucleotidiltransferasas
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Año:
2019
Tipo del documento:
Article