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

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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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.

Original languageEnglish (US)
Article numbere1011641
Pages (from-to)e1011641
JournalPLoS pathogens
Issue number9
Early online dateSep 1 2023
StatePublished - Sep 14 2023


  • Mitochondria
  • Animals
  • Picornaviridae/physiology
  • Swine
  • Humans
  • Nucleotidyltransferases/metabolism
  • DNA, Mitochondrial
  • Mice
  • Peptide Hydrolases
  • Endopeptidases

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Virology
  • Parasitology
  • Microbiology
  • Immunology


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