Vesicle-associated membrane protein 5 is an intrinsic defense factor for embryonic stem cells against coronaviruses

Huijun Dong, Zihang Pan, Pengtao Jiao, Fei Ye, Qi Peng, Yanying Yu, Xinyuan Lai, Huan Li, Zhao Guan, Juan Deng, Tao Shen, Wenjie Tan, Yi Shi, Qiang Ding, Jianyuan Luo, Tong Li, Hui Zhuang and Kuanhui Xiang ()
Additional contact information
Huijun Dong: Peking University Health Science Center
Zihang Pan: Peking University Health Science Center
Pengtao Jiao: Chinese Academy of Agricultural Sciences
Fei Ye: China CDC
Qi Peng: Chinese Academy of Sciences
Yanying Yu: Tsinghua University
Xinyuan Lai: Peking University Health Science Center
Huan Li: Peking University Health Science Center
Zhao Guan: Peking University Health Science Center
Juan Deng: Peking University Health Science Center
Tao Shen: Peking University Health Science Center
Wenjie Tan: China CDC
Yi Shi: Chinese Academy of Sciences
Qiang Ding: Tsinghua University
Jianyuan Luo: Peking University Health Science Center
Tong Li: Peking University Health Science Center
Hui Zhuang: Peking University Health Science Center
Kuanhui Xiang: Peking University Health Science Center

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Embryonic stem cells (ESCs) display a distinctive resistance against various viruses, irrespective of any interferon response. Nevertheless, the underlying mechanism of this resistance remains unclear. In this study, we identify vesicle-associated membrane protein 5 (VAMP5) as a potent cell-autonomous defense factor against coronaviruses, including SARS-CoV-2, with high expression levels observed in ESCs and mesoderm. VAMP5 not only exhibits functional conservation in restricting the replication of SARS-CoV-2 and its variants, as well as other highly pathogenic coronaviruses, but also shows efficacy in combating the replication of viruses from other families. Mechanistic investigations reveal that VAMP5 localizes to double membrane vesicles (DMVs) and impedes viral replication by relying on its vesicle-side C-terminal domain to interact with the viral non-structural protein 8 (NSP8), thus inhibiting the synthesis of negative-strand RNA. Our research demonstrates that VAMP5 in ESCs disrupts the protected environment of DMVs, which is essential for viral genome replication, and interacts with RNA replication complexes to defend against viral infection. This provides a novel strategy for developing broad-spectrum antiviral treatments.

Date: 2025
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DOI: 10.1038/s41467-025-61655-8

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