The antiviral role of TRIM25 in mammalian embryonic stem cells

Jie Zou; Yuxin Lin; Chunyan Wu; Yao Ji; Xuankai Zhao; Zhan Xu; Jingfei Gong; Zhiyuan Shi; Tianyang Luo; Xiaoling Xie; Yanan Jiang; Qi Tian; Shuqi Zhang; Yanxi Ji; Yuan Li; Zhenyu He; Shuchun Zhang; Liu Cao; Chun-Mei Li; Junyu Wu; Deyin Guo

doi:10.1016/j.virs.2026.07.011

August 2026

Citation: Jie Zou, Yuxin Lin, Chunyan Wu, Yao Ji, Xuankai Zhao, Zhan Xu, Jingfei Gong, Zhiyuan Shi, Tianyang Luo, Xiaoling Xie, Yanan Jiang, Qi Tian, Shuqi Zhang, Yanxi Ji, Yuan Li, Zhenyu He, Shuchun Zhang, Liu Cao, Chun-Mei Li, Junyu Wu, Deyin Guo. The antiviral role of TRIM25 in mammalian embryonic stem cells .VIROLOGICA SINICA, 2026, 41(4) : 820-831. http://dx.doi.org/10.1016/j.virs.2026.07.011

The antiviral role of TRIM25 in mammalian embryonic stem cells

Jie Zou ^a ,
Yuxin Lin ^b ,
Chunyan Wu ^a ,
Yao Ji ^a ,
Xuankai Zhao ^a ,
Zhan Xu ^a ,
Jingfei Gong ^a ,
Zhiyuan Shi ^a ,
Tianyang Luo ^a ,
Xiaoling Xie ^a ,
Yanan Jiang ^a ,
Qi Tian ^a ,
Shuqi Zhang ^a ,
Yanxi Ji ^a ,
Yuan Li ^a ,
Zhenyu He ^a ,
Shuchun Zhang ^a ,
Liu Cao ^{a
,,} ,
Chun-Mei Li ^{a
,,} ,
Junyu Wu ^{a
,,} ,
Deyin Guo ^{a,b,c
,,}

a. MOE Key Laboratory of Tropical Disease Control, Zhongshan School of Medicine, Sun Yat-sen University Shenzhen Campus, Shenzhen 518197, China;
b. Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou 510320, China;
c. State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510182, China

Corresponding author: Liu Cao, caoliu@mail.sysu.edu.cn
Chun-Mei Li, lichm8@mail.sysu.edu.cn
Junyu Wu, wujy68@mail.sysu.edu.cn
Deyin Guo, guo_deyin@gzlab.ac.cn
Received Date: 17 January 2026
Accepted Date: 28 July 2026
Available online: 30 July 2026

Abstract

Mammalian embryonic stem cells (ESCs), despite lacking functional interferon (IFN) signaling, are remarkably resistant to viral infection. However, the mechanistic basis of their antiviral defenses remains incompletely characterized. In this study, we investigated the antiviral functional role and molecular mechanism of tripartite motif-containing protein 25 (TRIM25), a well-known key driver of IFN-dependent innate immunity, in IFN-deficient mouse ESCs (mESCs). TRIM25 exhibited a broad spectrum of antiviral activity in mESCs. RNAi depletion or CRISPR-mediated knockout of TRIM25 markedly enhanced the replication and propagation of both encephalomyocarditis virus (EMCV) and vesicular stomatitis virus (VSV). Mechanistically, the antiviral activity of TRIM25 in mESCs is independent of both IFN production and constitutive ISG expression. In virus-infected mESCs, TRIM25 translocated from the nucleus to the cytoplasm and directly bound viral RNA, where it formed cytoplasmic condensates with GTPase-activating protein-binding protein 1 (G3BP1) that colocalized with dsRNA foci. Genetic perturbation of G3BP1 similarly compromised the antiviral defenses of mESCs, revealing an essential synergism between TRIM25 and stress granule components in restricting viral replication. Our study identifies TRIM25 as a pivotal RNA-sensing effector in ESCs, delineating a previously unrecognized IFN-independent axis of intrinsic immunity that bridges viral RNA surveillance with stress granule-mediated suppression, thereby expanding the paradigm of pluripotent cell-autonomous antiviral strategies.
- TRIM25
- , Embryonic stem cell
- , G3BP1
- , RNA-binding
- , RNA virus

Electronic Supplementary Material

10.1016j.virs.2026.07.011-ESM.docx
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