STING1 negatively regulates translation and replication of foot-and-mouth disease virus independently of interferon and is antagonized by the viral proteins 3C and 2B

Wenhua Shao; Wei Zhang; Zhitong Chen; Tingting Zhou; Xiaoyi Zhao; Hongyi Liu; Chuangwei Chen; Xingyan Dong; Weijun Cao; Zongsheng Zhao; Fan Yang; Zixiang Zhu; Haixue Zheng

doi:10.1016/j.virs.2026.04.007

April 2026

. doi: 10.1016/j.virs.2026.04.007

Citation: Wenhua Shao, Wei Zhang, Zhitong Chen, Tingting Zhou, Xiaoyi Zhao, Hongyi Liu, Chuangwei Chen, Xingyan Dong, Weijun Cao, Zongsheng Zhao, Fan Yang, Zixiang Zhu, Haixue Zheng. STING1 negatively regulates translation and replication of foot-and-mouth disease virus independently of interferon and is antagonized by the viral proteins 3C and 2B .VIROLOGICA SINICA, 2026, 41(2) : 355-370. http://dx.doi.org/10.1016/j.virs.2026.04.007

STING1不依赖干扰素负调控口蹄疫病毒的翻译和复制，并被病毒蛋白3C和2B拮抗

邵文华 ^a,b ,
张伟 ^b,, ,
陈治彤 ^b ,
周婷婷 ^b ,
赵晓义 ^b ,
刘泓屹 ^b ,
陈创伟 ^b ,
董星艳 ^b ,
曹伟军 ^b ,
赵宗胜 ^a,, ,
杨帆 ^b,, ,
朱紫祥 ^b,, ,
郑海学 ^b

a 石河子大学动物科技学院(新疆石河子 832001);
b 中国农业科学院兰州兽医研究所兰州大学动物医学与生物安全学院动物疫病防控全国重点实验室(中国兰州 730000)

通讯作者： 张伟, zhangwei09@caas.cn; 赵宗胜, zhaozongsh@sohu.com; 杨帆, yangfan02@caas.cn; 朱紫祥, zhuzixiang@caas.cn;
收稿日期： 2025-10-30
录用日期： 2026-04-15

摘要

口蹄疫病毒（FMDV）是一种高度传染性小RNA病毒，它通过多种策略来逃逸宿主先天免疫，其中病毒蛋白3C蛋白酶（3Cpro）和2B是关键的免疫拮抗因子。干扰素基因刺激因子 1（STING1）是一种关键的先天免疫接头分子，而其在FMDV感染中的作用和调控机制尚未完全阐明。本研究表明，STING1通过非干扰素（IFN）依赖机制抑制FMDV复制，而FMDV则通过3Cpro和2B降解STING1来拮抗这种抗病毒作用。在机制上，FMDV 3Cpro以蛋白酶活性依赖的方式介导STING1降解；这种STING1降解活性在脊髓灰质炎病毒、肠道病毒71型和柯萨奇病毒的3Cpro蛋白中是保守的，但在塞内卡病毒A中则不保守。相比之下，FMDV 2B在mRNA水平上抑制STING1表达，且3Cpro/2B介导的STING1下调均不依赖蛋白酶体、溶酶体或半胱天冬酶通路。此外，STING1稳定剂SB24011可增强内源性STING1表达，通过靶向病毒内部核糖体进入位点（IRES）介导的翻译，以剂量依赖的方式抑制FMDV复制，并表现出对多种小RNA病毒的广谱抗病毒活性。在体内实验中，SB24011治疗可减轻病毒诱导的组织病理损伤。综上所述，研究结果揭示了STING1对FMDV的新型非干扰素依赖性抗病毒作用，鉴定了3Cpro和2B为FMDV编码的STING1拮抗蛋白，并突出了SB24011作为广谱抗小RNA病毒治疗药物的潜力。
- 口蹄疫病毒
- , 干扰素刺激因子1
- , 3C蛋白酶
- , 非干扰素依赖
- , 抗病毒活性

STING1 negatively regulates translation and replication of foot-and-mouth disease virus independently of interferon and is antagonized by the viral proteins 3C and 2B

a. College of Animal Science and Technology, Shihezi University, Shihezi 832001, China;
b. State Key Laboratory of Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China

Corresponding author: Wei Zhang, zhangwei09@caas.cn Zongsheng Zhao, zhaozongsh@sohu.com Fan Yang, yangfan02@caas.cn Zixiang Zhu, zhuzixiang@caas.cn
Received Date: 30 October 2025
Accepted Date: 15 April 2026

Abstract

Foot-and-mouth disease virus (FMDV), a highly contagious picornavirus, employs multifaceted strategies to evade host innate immunity, with viral proteins 3C protease (3C^pro) and 2B serving as key immune antagonists. The stimulator of interferon genes 1 (STING1) is a critical innate immune adaptor; however, its role and regulatory mechanisms during FMDV infection remain incompletely understood. Here, we report that STING1 inhibits FMDV replication through an interferon (IFN)-independent mechanism, while FMDV counteracts this antiviral effect by degrading STING1 via 3C^pro and 2B. Mechanistically, FMDV 3C^pro mediates STING1 degradation in a protease activity-dependent manner; this STING1-degrading activity is conserved among 3C^pro proteins of poliovirus, enterovirus 71, and coxsackievirus, but not senecavirus A. In contrast, FMDV 2B suppresses STING1 expression at the mRNA level, and neither proteasomal, lysosomal, nor caspase pathways are involved in 3C^pro/2B-mediated STING1 downregulation. Furthermore, the STING1 stabilizer SB24011 enhances endogenous STING1 expression, dose-dependently inhibits FMDV replication by targeting viral internal ribosome entry site (IRES)-mediated translation, and exhibits broad-spectrum antiviral activity against multiple picornaviruses. In vivo, SB24011 treatment alleviates virus-induced histopathological lesions. Collectively, our findings reveal a novel IFN-independent antiviral role of STING1 against FMDV, identify 3C^pro and 2B as FMDV-encoded STING1 antagonists, and highlight the potential of SB24011 as a broad-spectrum anti-picornavirus therapeutic agent.
- Foot-and-mouth disease virus (FMDV)
- , STING1
- , 3C protease
- , Interferon-independent
- , Antiviral activity

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