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ORIGINAL RESEARCH article
Front. Immunol.
Sec. Viral Immunology
Volume 15 - 2024 |
doi: 10.3389/fimmu.2024.1403070
Pseudorabies virus tegument protein US2 antagonizes Antiviral innate immunity by targeting cGAS-STING signaling pathway
Provisionally accepted
Zhengjie Kong
1
Xing Chen
2*
Lele Gong
2*
Lele Wang
2*
Zhang Yifeng
1
Kaifeng Guan
1*
Wanzi Yao
1
Yu Kang
1*
Xinyi Lu
1*
Yuhang Zhang
2
Yongkun Du
2
Aijun Sun
2*
Guoqing Zhuang
2
Jianguo Zhao
3
Bo Wan
2
Gaiping Zhang
1*- 1 School of Advanced Agricultural Sciences, Peking University, Beijing, China
- 2 College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan Province, China
- 3 Institute of Zoology, Chinese Academy of Sciences (CAS), Beijing, Beijing, China
The cGAS-STING axis-mediated type I interferon pathway is a crucial strategy for host defense against DNA virus infection. Numerous evasion strategies developed by the pseudorabies virus (PRV) counteract host antiviral immunity. To what extent PRV-encoded proteins evade the cGAS-STING signaling pathway is unknown. Using 2 US2 stably expressing cell lines and US2-deficient PRV model, we revealed that the PRV tegument protein US2 reduces STING protein stability and downregulates STING-mediated antiviral signaling. To promote K48-linked ubiquitination and STING degradation, US2 interacts with the LBD structural domain of STING and recruits the E3 ligase TRIM21. TRIM21 deficiency consistently strengthens the host antiviral immune response brought on by PRV infection. Additionally, US2-deficient PRV is less harmful in mice. Our study implies that PRV US2 inhibits IFN signaling by a new mechanism that selectively targets STING while successfully evading the host antiviral response. As a result, the present study reveals a novel strategy by which PRV evades host defense and offers explanations for why the Bartha-K61 classical vaccine strain failed to offer effective defense against PRV variant strains in China, indicating that US2 may be a key target for developing gene-deficient PRV vaccines.
Keywords: pseudorabies virus, cGAS-STING, tegument protein US2, TRIM21, immune escape
Received: 18 Mar 2024; Accepted: 30 Apr 2024.
Copyright: © 2024 Kong, Chen, Gong, Wang, Yifeng, Guan, Yao, Kang, Lu, Zhang, Du, Sun, Zhuang, Zhao, Wan and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Xing Chen, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450002, Henan Province, China
Lele Gong, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450002, Henan Province, China
Lele Wang, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450002, Henan Province, China
Kaifeng Guan, School of Advanced Agricultural Sciences, Peking University, Beijing, China
Yu Kang, School of Advanced Agricultural Sciences, Peking University, Beijing, China
Xinyi Lu, School of Advanced Agricultural Sciences, Peking University, Beijing, China
Aijun Sun, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450002, Henan Province, China
Gaiping Zhang, School of Advanced Agricultural Sciences, Peking University, Beijing, China
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