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

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 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 ^a,b ,
Wei Zhang ^{b
,,} ,
Zhitong Chen ^b ,
Tingting Zhou ^b ,
Xiaoyi Zhao ^b ,
Hongyi Liu ^b ,
Chuangwei Chen ^b ,
Xingyan Dong ^b ,
Weijun Cao ^b ,
Zongsheng Zhao ^{a
,,} ,
Fan Yang ^{b
,,} ,
Zixiang Zhu ^{b
,,} ,
Haixue Zheng ^b

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
Available online: 17 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

Electronic Supplementary Material

10.1016j.virs.2026.04.007-ESM.docx
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