ASFV pA151R negatively regulates type I IFN production via degrading E3 ligase TRAF6

You Li; Li Huang; Hui Li; Yingqi Zhu; Zilong Yu; Xiaojie Zheng; Changjiang Weng; Wen-Hai Feng

doi:10.3389/fimmu.2024.1339510

ASFV pA151R negatively regulates type I IFN production via degrading E3 ligase TRAF6

Front Immunol. 2024 Feb 21:15:1339510. doi: 10.3389/fimmu.2024.1339510. eCollection 2024.

Authors

You Li^{1

2

3

4}, Li Huang⁵, Hui Li^{1

2

3

4}, Yingqi Zhu^{1

2

3

4}, Zilong Yu^{1

2

3

4}, Xiaojie Zheng^{1

2

3

4}, Changjiang Weng⁵, Wen-Hai Feng^{1

2

3

4}

Affiliations

¹ State Key Laboratory of Animal Biotech Breeding, China Agricultural University, Beijing, China.
² Frontiers Science Center for Molecular Design Breeding, College of Biological Sciences, China Agricultural University, Beijing, China.
³ Ministry of Agriculture Key Laboratory of Soil Microbiology, College of Biological Sciences, China Agricultural University, Beijing, China.
⁴ Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing, China.
⁵ State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin, China.

Abstract

African swine fever (ASF) caused by African swine fever virus (ASFV) is a highly mortal and hemorrhagic infectious disease in pigs. Previous studies have indicated that ASFV modulates interferon (IFN) production. In this study, we demonstrated that ASFV pA151R negatively regulated type I IFN production. Ectopic expression of pA151R dramatically inhibited K63-linked polyubiquitination and Ser172 phosphorylation of TANK-binding kinase 1 (TBK1). Mechanically, we demonstrated that E3 ligase TNF receptor-associated factor 6 (TRAF6) participated in the ubiquitination of TBK1 in cGAS-STING signaling pathway. We showed that pA151R interacted with TRAF6 and degraded it through apoptosis pathway, leading to the disruption of TBK1 and TRAF6 interaction. Moreover, we clarified that the amino acids H102, C109, C132, and C135 in pA151R were crucial for pA151R to inhibit type I interferon production. In addition, we verified that overexpression of pA151R facilitated DNA virus Herpes simplex virus 1 (HSV-1) replication by inhibiting IFN-β production. Importantly, knockdown of pA151R inhibited ASFV replication and enhanced IFN-β production in porcine alveolar macrophages (PAMs). Our findings will help understand how ASFV escapes host antiviral immune responses and develop effective ASFV vaccines.

Keywords: ASFV; TBK1; TRAF6; pA151R; type I IFN.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

African Swine Fever Virus*
African Swine Fever*
Animals
Swine
TNF Receptor-Associated Factor 6
Ubiquitin-Protein Ligases
Ubiquitination

Substances

Ubiquitin-Protein Ligases
TNF Receptor-Associated Factor 6

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the National Natural Science Foundation of China (Grant No. 32172869), China.