2. Academic Validation
  3. Mutations at site 207 of influenza a virus NS1 protein switch its function in regulating RIG-I-like receptors mediated antiviral responses

Mutations at site 207 of influenza a virus NS1 protein switch its function in regulating RIG-I-like receptors mediated antiviral responses

  • Antiviral Res. 2023 May 23;105641. doi: 10.1016/j.antiviral.2023.105641.
Xingbo Wang 1,  Lulu Lin 1,  Zhen Chen 2,  Wei Si 3,  Yan Yan 1,  Weiren Dong 1,  Yulan Jin 1,  Yu Huang 4,  Jiyong Zhou 5
Affiliations

Affiliations

  • 1 MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou, 310058, PR China.
  • 2 Institute of Animal Husbandry and Veterinary, Fujian Academy of Agricultural Sciences, Fuzhou, 350013, PR China.
  • 3 MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou, 310058, PR China; College of Animal Science and Technology, Guangxi University, Nanning, 530004, PR China.
  • 4 College of Animal Science and Technology, Guangxi University, Nanning, 530004, PR China.
  • 5 MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou, 310058, PR China; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University, Hangzhou, 310003, PR China. Electronic address: [email protected].
PMID: 37230297 DOI: 10.1016/j.antiviral.2023.105641
Abstract

RIG-I-like receptors (RLRs), retinoic acid inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), are Pattern Recognition Receptors through which cells initially sense pathogenic RNA and trigger interferon (IFN) signaling. Herein, we report that interferon induced protein 35 (IFI35) activates the ring finger protein 125 (RNF125)-UbcH5c-dependent degradation of RLRs and represses the recognition by RIG-I and MDA5 of viral RNA to inhibit innate immunity. Furthermore, IFI35 binds selectively to different subtypes of influenza A virus (IAV) nonstructural protein 1 (NS1) with asparagine residue207 (N207). Functionally, the NS1(N207)-IFI35 interaction restores the activity of RLRs, and IAV with NS1(non-N207) showed high pathogenicity in mice. Big data analysis showed that the 21st century pandemic IAV are almost all characterized by NS1 protein with non-N207. Collectively, our data uncovered the mechanism of IFI35 restricting the activation of RLRs and provides a new drug target comprising the NS1 protein of different IAV subtypes.

Keywords

IFI35; Influenza a virus; K48-linked ubiquitination; NS1; RIG-I-like receptors; RNA recognition.

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