African swine fever virus S273R protein antagonizes type I interferon production by interfering with TBK1 and IRF3 interaction

Hui Li; Xiaojie Zheng; You Li; Yingqi Zhu; Yangyang Xu; Zilong Yu; Wen-Hai Feng

doi:10.1016/j.virs.2023.08.009

African swine fever virus S273R protein antagonizes type I interferon production by interfering with TBK1 and IRF3 interaction

Virol Sin. 2023 Dec;38(6):911-921. doi: 10.1016/j.virs.2023.08.009. Epub 2023 Sep 1.

Authors

Hui Li¹, Xiaojie Zheng¹, You Li¹, Yingqi Zhu¹, Yangyang Xu¹, Zilong Yu¹, Wen-Hai Feng²

Affiliations

¹ State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China; Frontiers Science Center for Molecular Design Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China; Ministry of Agriculture Key Laboratory of Soil Microbiology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China; Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
² State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China; Frontiers Science Center for Molecular Design Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China; Ministry of Agriculture Key Laboratory of Soil Microbiology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China; Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing 100193, China. Electronic address: whfeng@cau.edu.cn.

Abstract

African swine fever (ASF) is originally reported in East Africa as an acute hemorrhagic fever. African swine fever virus (ASFV) is a giant and complex DNA virus with icosahedral structure and encodes a variety of virulence factors to resist host innate immune response. S273R protein (pS273R), as a SUMO-1 specific cysteine protease, can affect viral packaging by cutting polymeric proteins. In this study, we found that pS273R was an important antagonistic viral factor that suppressed cGAS-STING-mediated type I interferon (IFN-I) production. A detailed analysis showed that pS273R inhibited IFN-I production by interacting with interferon regulatory factor 3 (IRF3). Subsequently, we showed that pS273R disrupted the association between TBK1 and IRF3, leading to the repressed IRF3 phosphorylation and dimerization. Deletion and point mutation analysis verified that pS273R impaired IFN-I production independent of its cysteine protease activity. These findings will help us further understand ASFV pathogenesis.

Keywords: African swine fever virus (ASFV); IRF3; S273R; TBK1; Type I interferon (IFN-I); cGAS-STING.

MeSH terms

African Swine Fever Virus* / genetics
African Swine Fever*
Animals
Cysteine Proteases* / metabolism
Interferon Regulatory Factor-3
Interferon Type I* / metabolism
Protein Serine-Threonine Kinases / genetics
Swine

Substances

Protein Serine-Threonine Kinases
Interferon Regulatory Factor-3
Interferon Type I
Cysteine Proteases