Species-specific cleavage of cGAS by picornavirus protease 3C disrupts mitochondria DNA-mediated immune sensing

RNA viruses cause numerous infectious diseases in humans and animals. The crosstalk between RNA viruses and the innate DNA sensing pathways attracts increasing attention. Recent studies showed that the cGAS-STING pathway plays an important role in restricting RNA viruses via mitochondria DNA (mtDNA)...

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Bibliographic Details
Published in:PLoS pathogens 2023-09, Vol.19 (9), p.e1011641
Main Authors: Yan, Ya, Wu, Lei, Yuan, Ye, Wang, Haiwei, Yin, Hongyan, Li, Minjie, Chai, Lvye, Liang, Ruiying, Liu, Yanjie, Zhao, Dongming, Xing, Junji, Li, Pingwei, Li, Xin
Format: Article
Language:English
Subjects:
Biological response modifiers
Biology and Life Sciences
Chikungunya virus
Cleavage
CRISPR
Dengue fever
Deoxyribonucleic acid
DNA
DNA biosynthesis
DNA viruses
Ethylenediaminetetraacetic acid
Foot & mouth disease
Immune response
Immune system
Infections
Infectious diseases
Innate immunity
Interferon
Kinases
Mitochondria
Mitochondrial DNA
Protease
Proteases
Proteins
Research and Analysis Methods
Ribonucleic acid
RNA
RNA viruses
Transfection
Viruses
Zika virus
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Summary:RNA viruses cause numerous infectious diseases in humans and animals. The crosstalk between RNA viruses and the innate DNA sensing pathways attracts increasing attention. Recent studies showed that the cGAS-STING pathway plays an important role in restricting RNA viruses via mitochondria DNA (mtDNA) mediated activation. However, the mechanisms of cGAS mediated innate immune evasion by RNA viruses remain unknown. Here, we report that seneca valley virus (SVV) protease 3C disrupts mtDNA mediated innate immune sensing by cleaving porcine cGAS (pcGAS) in a species-specific manner. Mechanistically, a W/Q motif within the N-terminal domain of pcGAS is a unique cleavage site recognized by SVV 3C. Three conserved catalytic residues of SVV 3C cooperatively contribute to the cleavage of pcGAS, but not human cGAS (hcGAS) or mouse cGAS (mcGAS). Additionally, upon SVV infection and poly(dA:dT) transfection, pcGAS and SVV 3C colocalizes in the cells. Furthermore, SVV 3C disrupts pcGAS-mediated DNA binding, cGAMP synthesis and interferon induction by specifically cleaving pcGAS. This work uncovers a novel mechanism by which the viral protease cleaves the DNA sensor cGAS to evade innate immune response, suggesting a new antiviral approach against picornaviruses.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1011641