2. Academic Validation
  3. ARRDC3 promotes lysosome-mediated YAP degradation to inhibit enterovirus replication

ARRDC3 promotes lysosome-mediated YAP degradation to inhibit enterovirus replication

  • Virol Sin. 2025 Aug;40(4):658-668. doi: 10.1016/j.virs.2025.07.009.
Xia Huang 1,  Siyuan Wang 2,  Yan Huang 1,  Yue Wang 1,  Guangchao Zang 1,  Yan Liang 1,  Juntong Liu 1,  Xinyue Han 1,  Jingjing Liao 1,  Tingting Chen 3,  Nan Lu 4,  Guangyuan Zhang 5
Affiliations

Affiliations

  • 1 Pathogen Biology and Immunology Laboratory, Lab Teaching & Management Center, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China.
  • 2 Department of Thyroid, Breast and Vascular Surgery, Xi Jing Hospital, Air Force Medical University, Xi'an, 710032, China.
  • 3 Pathogen Biology and Immunology Laboratory, Lab Teaching & Management Center, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China. Electronic address: cherrychen@cqmu.edu.cn.
  • 4 Pathogen Biology and Immunology Laboratory, Lab Teaching & Management Center, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China. Electronic address: ficus@cqmu.edu.cn.
  • 5 Pathogen Biology and Immunology Laboratory, Lab Teaching & Management Center, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China. Electronic address: sanqinyouthzhang@126.com.
PMID: 40701343 DOI: 10.1016/j.virs.2025.07.009
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.

Keywords

Arrestin domain containing 3 (HPIV3); Enterovirus A71 (EV-A71); Enterovirus D68 (EV-D68); Yes-associated protein (YAP).

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