Classical swine fever virus NS5A protein antagonizes innate immune response by inhibiting the NF-κB signaling

Jinfu Sun; Jiaying Li; Liming Li; Haixiao Yu; Ping Ma; Yingnan Wang; Jinqi Zhu; Zezhong Feng; Changchun Tu

doi:10.1016/j.virs.2023.09.002

December 2023

. doi: 10.1016/j.virs.2023.09.002

Citation: Jinfu Sun, Jiaying Li, Liming Li, Haixiao Yu, Ping Ma, Yingnan Wang, Jinqi Zhu, Zezhong Feng, Changchun Tu. Classical swine fever virus NS5A protein antagonizes innate immune response by inhibiting the NF-κB signaling .VIROLOGICA SINICA, 2023, 38(6) : 900-910. http://dx.doi.org/10.1016/j.virs.2023.09.002

猪瘟病毒NS5A蛋白通过抑制NF-κB信号对抗宿主天然免疫反应

孙金福 ^a,, ,
李佳莹 ^a ,
李黎明 ^a ,
于海啸 ^a ,
马平 ^a ,
王英楠 ^a ,
朱瑾琪 ^a ,
冯泽众 ^a ,
涂长春 ^b,c,,

东北大学生命科学与健康学院

通讯作者： 孙金福, sunjinfu@mail.neu.edu.cn; 涂长春, changchun_tu@hotmail.com
收稿日期： 2023-02-11
录用日期： 2023-09-08

摘要

猪瘟病毒NS5A蛋白是一个多功能蛋白，参与病毒基因组复制、蛋白翻译、病毒粒子装配并调控细胞信号。研究显示NS5A抑制NF-κB信号，但是抑制NF-κB信号的分子机制尚未阐明。本研究证实NS5A与NEMO相互作用并诱导NEMO K27连接的多聚泛素化和蛋白酶体的降解。此外，NEMO锌指域是其与NS5A相互作用必需的，NEMO锌指域是NEMO K63多聚泛素化进而激活NF-κB信号必需区域。NEMO K63多聚泛素化分析显示，NS5A抑制NEMO K63多聚泛素化。这些数据表明，猪瘟病毒NS5A蛋白通过介导NEMO蛋白酶体的降解及阻碍NEMO K63多聚泛素化抑制TNF-α诱导的NF-κB信号。
- 猪瘟病毒
- , NS5A蛋白
- , NF-κB信号
- , NF-κB必需调节子(NEMO)
- , 多聚泛素化

Classical swine fever virus NS5A protein antagonizes innate immune response by inhibiting the NF-κB signaling

Jinfu Sun ^a,, ,
Jiaying Li ^a ,
Liming Li ^a ,
Haixiao Yu ^a ,
Ping Ma ^a ,
Yingnan Wang ^a ,
Jinqi Zhu ^a ,
Zezhong Feng ^a ,
Changchun Tu ^b,c,,

a. Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang, 110169, China;
b. Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, China;
c. Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonoses, Yangzhou University, Yangzhou, 225009, China

Corresponding author: Jinfu Sun, sunjinfu@mail.neu.edu.cn Changchun Tu, changchun_tu@hotmail.com
Received Date: 11 February 2023
Accepted Date: 08 September 2023

Abstract

The NS5A non-structural protein of classical swine fever virus (CSFV) is a multifunctional protein involved in viral genomic replication, protein translation, assembly of infectious virus particles, and regulation of cellular signaling pathways. Previous report showed that NS5A inhibited nuclear factor kappa B (NF-κB) signaling induced by poly(I:C); however, the mechanism involved has not been elucidated. Here, we reported that NS5A directly interacted with NF-κB essential modulator (NEMO), a regulatory subunit of the IκB kinase (IKK) complex, to inhibit the NF-κB signaling pathway. Further investigations showed that the zinc finger domain of NEMO and the aa 126–250 segment of NS5A are essential for the interaction between NEMO and NS5A. Mechanistic analysis revealed that NS5A mediated the proteasomal degradation of NEMO. Ubiquitination assay showed that NS5A induced the K27-linked but not the K48-linked polyubiquitination of NEMO for proteasomal degradation. In addition, NS5A blocked the K63-linked polyubiquitination of NEMO, thus inhibiting IKK phosphorylation, IκBα degradation, and NF-κB activation. These findings revealed a novel mechanism by which CSFV inhibits host innate immunity, which might guide the drug design against CSFV in the future.
- Classical swine fever virus (CSFV)
- , NS5A
- , NF-κB signaling
- , NEMO
- , Polyubiquitination
- , Proteasomal degradation

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