ARRDC3 promotes lysosome-mediated YAP degradation to inhibit enterovirus replication

Xia Huang; Siyuan Wang; Yan Huang; Yue Wang; Guangchao Zang; Yan Liang; Juntong Liu; Xinyue Han; Jingjing Liao; Tingting Chen; Nan Lu; Guangyuan Zhang

doi:10.1016/j.virs.2025.07.009

August 2025

. doi: 10.1016/j.virs.2025.07.009

Citation: Xia Huang, Siyuan Wang, Yan Huang, Yue Wang, Guangchao Zang, Yan Liang, Juntong Liu, Xinyue Han, Jingjing Liao, Tingting Chen, Nan Lu, Guangyuan Zhang. ARRDC3 promotes lysosome-mediated YAP degradation to inhibit enterovirus replication .VIROLOGICA SINICA, 2025, 40(4) : 658-668. http://dx.doi.org/10.1016/j.virs.2025.07.009

ARRDC3促进YAP溶酶体途径降解从而抑制肠道病毒复制

黄霞 ^a ,
王思源 ^b ,
黄研 ^a ,
王悦 ^a ,
臧广超 ^a ,
梁岩 ^a ,
刘俊彤 ^a ,
韩欣玥 ^a ,
廖晶晶 ^a ,
陈婷婷 ^a,, ,
卢楠 ^a,, ,
张光媛 ^a,,

a 重庆医科大学, 基础医学院, 实验教学管理中心, 病原生物学与免疫学实验室;
b 空军军医大学西京医院甲乳血管外科

通讯作者： 陈婷婷, cherrychen@cqmu.edu.cn; 卢楠, ficus@cqmu.edu.cn; 张光媛, sanqinyouthzhang@126.com
收稿日期： 2025-05-10
录用日期： 2025-07-18

摘要

肠道病毒68型（EV-D68）和71型（EV-A71）近年来在全球多地区流行，构成重大公共卫生威胁，然而其致病机制尚未阐明。含α-arrestins结构域蛋白3（ARRDC3）在调控葡萄糖代谢、癌症发展和炎症反应中发挥重要作用，但其是否参与先天抗病毒免疫尚不明确。本研究发现，肠道病毒感染可诱导细胞中ARRDC3 在转录和翻译水平表达上调，进而抑制病毒复制。进一步研究表明，ARRDC3通过溶酶体途径降解Hippo信号通路的核心效应分子——Yes相关蛋白（YAP）。在肠道病毒感染后期，YAP通过抑制干扰素通路促进病毒复制，且该作用不依赖于其转录活性。此外，ARRDC3-YAP通路在人副流感病毒3型（HPIV3）和水疱性口炎病毒(VSV)等多种病毒感染中均表现出显著的抗病毒作用。综上，本研究揭示了ARRDC3介导的YAP靶向降解在先天抗病毒免疫应答中的关键作用，为抗病毒治疗提供了新的靶点。
- 肠道病毒68型（EV-D68）
- , 肠道病毒71型（EV-A71）
- , 含α-arrestins结构域蛋白3（ARRDC3）
- , Yes相关蛋白（YAP）

ARRDC3 promotes lysosome-mediated YAP degradation to inhibit enterovirus replication

Xia Huang ^a ,
Siyuan Wang ^b ,
Yan Huang ^a ,
Yue Wang ^a ,
Guangchao Zang ^a ,
Yan Liang ^a ,
Juntong Liu ^a ,
Xinyue Han ^a ,
Jingjing Liao ^a ,
Tingting Chen ^a,, ,
Nan Lu ^a,, ,
Guangyuan Zhang ^a,,

a. Pathogen Biology and Immunology Laboratory, Lab Teaching & Management Center, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China;
b. Department of Thyroid, Breast and Vascular Surgery, Xi Jing Hospital, Air Force Medical University, Xi'an, 710032, China

Corresponding author: Tingting Chen, cherrychen@cqmu.edu.cn Nan Lu, ficus@cqmu.edu.cn Guangyuan Zhang, sanqinyouthzhang@126.com
Received Date: 10 May 2025
Accepted Date: 18 July 2025

Abstract

Enterovirus D68 (EV-D68) and enterovirus A71 (EV-A71) are two major types of enteroviruses that pose emerging challenges to public health and have the potential to cause outbreaks, yet their pathogenic mechanisms remain largely unexplored. Arrestin domain containing 3 (ARRDC3) is a vital regulator of glucose metabolism, cancer development, and inflammation. Whether ARRDC3 contributes to innate antiviral immunity is undefined. Here, we found that enterovirus infection induces ARRDC3 expression at both the mRNA and protein levels, thereby inhibiting enterovirus replication. Moreover, we demonstrate that the expression of Yes-associated protein (YAP), a key effector of the Hippo pathway, is severely downregulated by ARRDC3 via lysosomal pathway. YAP facilitates enterovirus replication by suppressing the interferon pathway during the later stage of enterovirus infection, independent of its transcriptional activity. Finally, the ARRDC3-YAP pathway exhibits a broad-spectrum antiviral effect in various viral infections, including those caused by human parainfluenza virus type 3 (HPIV3) and vesicular stomatitis virus (VSV). Collectively, our results identify the critical role of ARRDC3 and its negative regulatory effect on YAP in the innate antiviral response, suggesting a novel therapeutic strategy against virus infection.
- Enterovirus D68 (EV-D68)
- , Enterovirus A71 (EV-A71)
- , Arrestin domain containing 3 (HPIV3)
- , Yes-associated protein (YAP)

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