National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China.
Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China.
PLoS Pathog. 2023 Sep 14;19(9):e1011641. doi: 10.1371/journal.ppat.1011641. eCollection 2023 Sep.
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.
RNA 病毒会引起人类和动物的多种传染病。RNA 病毒与先天 DNA 感应途径之间的相互作用引起了越来越多的关注。最近的研究表明，cGAS-STING 途径通过线粒体 DNA（mtDNA）介导的激活在限制 RNA 病毒方面发挥着重要作用。然而，RNA 病毒通过 cGAS 介导的先天免疫逃避的机制尚不清楚。在这里，我们报告称，塞内卡谷病毒（SVV）蛋白酶 3C 通过以种属特异性的方式切割猪 cGAS（pcGAS），破坏 mtDNA 介导的先天免疫感应。在机制上，pcGAS 中 N 端结构域内的 W/Q 基序是 SVV 3C 识别的独特切割位点。SVV 3C 的三个保守催化残基协同作用于 pcGAS 的切割，但不切割人 cGAS（hcGAS）或小鼠 cGAS（mcGAS）。此外，在 SVV 感染和多聚（dA:dT）转染后，pcGAS 和 SVV 3C 在细胞中共定位。此外，SVV 3C 通过特异性切割 pcGAS 破坏 pcGAS 介导的 DNA 结合、cGAMP 合成和干扰素诱导。这项工作揭示了病毒蛋白酶切割 DNA 传感器 cGAS 以逃避先天免疫反应的新机制，为针对小 RNA 病毒的新型抗病毒方法提供了思路。
