African swine fever virus MGF360-4L protein attenuates type I interferon response by suppressing the phosphorylation of IRF3

Front Immunol. 2024 Sep 13:15:1382675. doi: 10.3389/fimmu.2024.1382675. eCollection 2024.

Abstract

African swine fever (ASF) is a highly contagious and lethal disease of swine caused by African swine fever virus (ASFV), and the mortality rate caused by virulent stains can approach 100%. Many ASFV viral proteins suppress the interferon production to evade the host's innate immune responses. However, whether ASFV MGF360-4L could inhibit type I interferon (IFN-I) signaling pathway and the underlying molecular mechanisms remain unknown. Our study, indicated that ASFV MGF360-4L could negatively regulates the cGAS-STING mediated IFN-I signaling pathway. Overexpressing ASFV MGF360-4L could inhibit the cGAS/STING signaling pathway by inhibiting the interferon-β promoter activity, which was induced by cGAS/STING, TBK1, and IRF3-5D, and further reduced the transcriptional levels of ISG15, ISG54, ISG56, STAT1, STAT2, and TYK2. Confocal microscopy and immunoprecipitation revealed that MGF360-4L co-localized and interacted with IRF3, and WB revealed that ASFV MGF360-4L suppressed the phosphorylation of IRF3. 4L-F2 (75-162 aa) and 4L-F3 (146-387 aa) were the crucial immunosuppressive domains and sites. Altogether, our study reveals ASFV MGF360-4L inhibited cGAS-STING mediated IFN-I signaling pathways, which provides insights into an evasion strategy of ASFV involving in host's innate immune responses.

Keywords: African swine fever virus; MGF360-4L; phosphorylation; suppress; type I interferon.

MeSH terms

  • African Swine Fever Virus* / immunology
  • African Swine Fever* / immunology
  • African Swine Fever* / virology
  • Animals
  • HEK293 Cells
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immune Evasion
  • Immunity, Innate
  • Interferon Regulatory Factor-3* / metabolism
  • Interferon Type I* / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Nucleotidyltransferases / metabolism
  • Phosphorylation
  • Signal Transduction*
  • Swine
  • Viral Proteins* / metabolism

Substances

  • Interferon Regulatory Factor-3
  • Interferon Type I
  • Viral Proteins
  • Membrane Proteins
  • IRF3 protein, human
  • Nucleotidyltransferases

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Key Research and Development Program of China (2021YFD1801200) and the Yunnan Key Research and Development Project (202103AC100001), the Earmarked Fund for CARS (CARS36), and the Agricultural Science and Technology Innovation Program (no. ASTIP‐IAS‐11).