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

文献类型： 外文期刊

第一作者： Yan, Ya

作者： Yan, Ya;Wu, Lei;Yuan, Ye;Yin, Hongyan;Li, Minjie;Chai, Lvye;Li, Xin;Yan, Ya;Wu, Lei;Yuan, Ye;Yin, Hongyan;Li, Minjie;Chai, Lvye;Li, Xin;Wang, Haiwei;Zhao, Dongming;Liang, Ruiying;Liu, Yanjie;Xing, Junji;Xing, Junji;Xing, Junji;Li, Pingwei

作者机构：

期刊名称：PLOS PATHOGENS （ 影响因子：6.7； 五年影响因子：6.7 ）

ISSN： 1553-7366

年卷期： 2023 年 19 卷 9 期

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收录情况： SCI

摘要： 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 approaches against picornaviruses. While the effect of cGAS on counteracting DNA viruses has been extensively studied, how cGAS restricts RNA viruses and how RNA viruses combat cGAS-mediated immune surveillance are largely unknown. Here, we show that picornavirus, seneca valley virus (SVV), infection causes the leakage of mitochondrial DNA into cytosol for cGAS activation, while SVV 3C protease cleaves porcine cGAS (pcGAS) in a species-specific manner to disrupt pcGAS-mediated DNA sensing, cGAMP synthesis and interferon induction. Importantly, we identify a W/Q motif within the N-terminal domain of pcGAS, which is unique among other species for SVV 3C cleavage. Three conserved catalytic residues of SVV 3C cooperatively contribute to the cleavage of pcGAS. These findings unravel a novel strategy for viral evasion of cGAS-mediated innate restriction.

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