MARCH8 attenuates cGAS-mediated innate immune responses through ubiquitylation.
Sci Signal
; 15(732): eabk3067, 2022 05 03.
Article
em En
| MEDLINE
| ID: mdl-35503863
ABSTRACT
Cyclic GMP-AMP synthase (cGAS) binds to microbial and self-DNA in the cytosol and synthesizes cyclic GMP-AMP (cGAMP), which activates stimulator of interferon genes (STING) and downstream mediators to elicit an innate immune response. Regulation of cGAS activity is essential for immune homeostasis. Here, we identified the E3 ubiquitin ligase MARCH8 (also known as MARCHF8, c-MIR, and RNF178) as a negative regulator of cGAS-mediated signaling. The immune response to double-stranded DNA was attenuated by overexpression of MARCH8 and enhanced by knockdown or knockout of MARCH8. MARCH8 interacted with the enzymatically active core of cGAS through its conserved RING-CH domain and catalyzed the lysine-63 (K63)-linked polyubiquitylation of cGAS at Lys411. This polyubiquitylation event inhibited the DNA binding ability of cGAS, impaired cGAMP production, and attenuated the downstream innate immune response. Furthermore, March8-deficient mice were less susceptible than their wild-type counterparts to herpes simplex virus 1 (HSV-1) infection. Together, our findings reveal a mechanism underlying the functional regulation of cGAS and the fine-tuning of the innate immune response.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ubiquitina-Proteína Ligases
/
Herpes Simples
/
Nucleotidiltransferases
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Sci Signal
Assunto da revista:
CIENCIA
/
FISIOLOGIA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China