African swine fever virus M1249L protein antagonizes type I interferon production via suppressing phosphorylation of TBK1 and degrading IRF3

  • Virus Res. 2022 Oct 2:319:198872. doi: 10.1016/j.virusres.2022.198872.
Shuai Cui  1 ,  Yang Wang  1 ,  Xintao Gao  2 ,  Ting Xin  1 ,  Xixi Wang  3 ,  Hainan Yu  1 ,  Shiyu Chen  1 ,  Yajun Jiang  1 ,  Qing Chen  4 ,  Fei Jiang  5 ,  Dongyue Wang  5 ,  Xiaoyu Guo  6 ,  Hong Jia  7 ,  Hongfei Zhu  8
Affiliations
  • 1. Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China.
  • 2. Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing, China.
  • 3. Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  • 4. Beijing University of Agriculture, Beijing, China.
  • 5. China Animal Disease Control Center, Beijing, China.
  • 6. Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China. Electronic address: [email protected].
  • 7. Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China. Electronic address: [email protected].
  • 8. Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China. Electronic address: [email protected].
PMID: 35853521 DOI: 10.1016/j.virusres.2022.198872
Abstract

Cyclic GMP-AMP Synthase (cGAS) is a major DNA sensor. The recognition of cytosolic DNA by cGAS triggers a robust innate immune response that restricts the replication of diverse viral pathogens through the type I interferon (IFN) and nuclear factor-κB (NF-κB) pathways. African swine fever virus (ASFV) is a large and complex DNA virus reported to strongly inhibit the cGAS-STING signaling pathway. Herein, 12 ASFV structural proteins were screened to determine their effects on the cGAS-STING pathway. Ectopic expression of the ASFV caspid protein M1249L significantly inhibited the IFN-β promoter activity induced by the cGAS-STING pathway in a dose-dependent manner. And it could also downregulate the levels of IFN-β and several interferon-stimulating genes (ISGs) induced by cGAS-STING and 2'3'-cGAMP. Moreover, ASFV M1249L also suppressed phosphorylation of TBK1 by cGAS and STING overexpression. Further study showed that M1249L co-localized and interacted with interferon regulatory factor 3 (IRF3), which led to induce IRF3 degradation by lysosomal pathway. Taken together, our study revealed a novel strategy utilized by ASFV for cGAS-STING-related immune evasion.

Keywords
African swine fever virus; IRF3; Innate immunity; M1249L; TBK1.
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