African swine fever virus pB475L evades host antiviral innate immunity via targeting STAT2 to inhibit IFN-I signaling

Zhao Huang; Zhanzhuo Mai; Cuiying Kong; Jianyi You; Sizhan Lin; Chenyang Gao; WenBo Zhang; Xiongnan Chen; Qingmei Xie; Heng Wang; Shengqiu Tang; Pei Zhou; Lang Gong; Guihong Zhang

doi:10.1016/j.jbc.2024.107472

African swine fever virus pB475L evades host antiviral innate immunity via targeting STAT2 to inhibit IFN-I signaling

J Biol Chem. 2024 Jul;300(7):107472. doi: 10.1016/j.jbc.2024.107472. Epub 2024 Jun 13.

Authors

Zhao Huang¹, Zhanzhuo Mai², Cuiying Kong³, Jianyi You², Sizhan Lin², Chenyang Gao², WenBo Zhang², Xiongnan Chen¹, Qingmei Xie⁴, Heng Wang⁵, Shengqiu Tang⁶, Pei Zhou⁷, Lang Gong⁸, Guihong Zhang⁹

Affiliations

¹ Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China; Guangdong Provincial Key Laboratory of Utilization and Conservation of Food and Medicinal Resources in Northern Region, Shaoguan University, Shaoguan, China; African Swine Fever Regional Laboratory of China, South China Agricultural University, Guangzhou, China.
² Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China; African Swine Fever Regional Laboratory of China, South China Agricultural University, Guangzhou, China.
³ Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
⁴ College of Animal Science, South China Agricultural University, Guangzhou, China.
⁵ Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China; African Swine Fever Regional Laboratory of China, South China Agricultural University, Guangzhou, China; Research Center for African Swine Fever Prevention and Control, South China Agricultural University, Guangzhou, China.
⁶ Guangdong Provincial Key Laboratory of Utilization and Conservation of Food and Medicinal Resources in Northern Region, Shaoguan University, Shaoguan, China.
⁷ Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China; African Swine Fever Regional Laboratory of China, South China Agricultural University, Guangzhou, China. Electronic address: [email protected].
⁸ Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China; African Swine Fever Regional Laboratory of China, South China Agricultural University, Guangzhou, China. Electronic address: [email protected].
⁹ Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China; Research Center for African Swine Fever Prevention and Control, South China Agricultural University, Guangzhou, China; Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong, China; Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China. Electronic address: [email protected].

Abstract

African swine fever virus (ASFV) causes severe disease in domestic pigs and wild boars, seriously threatening the development of the global pig industry. Type I interferon (IFN-I) is an important component of innate immunity, inducing the transcription and expression of antiviral cytokines by activating Janus-activated kinase-signal transducer and activator of transcription (STAT). However, the underlying molecular mechanisms by which ASFV antagonizes IFN-I signaling have not been fully elucidated. Therefore, using coimmunoprecipitation, confocal microscopy, and dual luciferase reporter assay methods, we investigated these mechanisms and identified a novel ASFV immunosuppressive protein, pB475L, which interacts with the C-terminal domain of STAT2. Consequently, pB475L inhibited IFN-I signaling by inhibiting STAT1 and STAT2 heterodimerization and nuclear translocation. Furthermore, we constructed an ASFV-B475L^7PM mutant strain by homologous recombination, finding that ASFV-B475L^7PM attenuated the inhibitory effects on IFN-I signaling compared to ASFV-WT. In summary, this study reveals a new mechanism by which ASFV impairs host innate immunity.

Keywords: African swine fever; pB475L; signal transducer and activator of transcription 2; type I interferon.

MeSH terms

African Swine Fever / genetics
African Swine Fever / immunology
African Swine Fever / metabolism
African Swine Fever / virology
African Swine Fever Virus* / genetics
African Swine Fever Virus* / immunology
Animals
HEK293 Cells
Humans
Immune Evasion
Immunity, Innate*
Interferon Type I* / immunology
Interferon Type I* / metabolism
STAT1 Transcription Factor / genetics
STAT1 Transcription Factor / metabolism
STAT2 Transcription Factor* / genetics
STAT2 Transcription Factor* / metabolism
Signal Transduction*
Swine
Viral Proteins* / genetics
Viral Proteins* / immunology
Viral Proteins* / metabolism

Substances

Interferon Type I
STAT1 Transcription Factor
STAT2 Transcription Factor
Viral Proteins
STAT2 protein, human