2. Academic Validation
  3. Ubiquitin-specific protease 5 promotes EV-A71 replication by de-ubiquitinating MAVS and IRF3

Ubiquitin-specific protease 5 promotes EV-A71 replication by de-ubiquitinating MAVS and IRF3

  • Virol Sin. 2025 Dec;40(6):910-920. doi: 10.1016/j.virs.2025.12.002.
Shumin Zhang 1,  Yuan Fang 2,  Shuai Ren 3,  Xuhua Zhang 2,  Chenggong Zheng 3,  Zhipeng Qin 3,  Wenqiang Wei 4,  Huabin Zheng 5,  Chuntian Li 5,  Zekun Wang 6,  Yujie Ren 7
Affiliations

Affiliations

  • 1 Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng 475004, China. Electronic address: [email protected].
  • 2 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng 475004, China.
  • 4 School of Basic Medical Sciences, Henan University, Kaifeng 475004, China.
  • 5 Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng 475004, China; The First Affiliated Hospital of Henan University, Henan University, Kaifeng 475004, China.
  • 6 Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng 475004, China; State Key Laboratory of Antiviral Drugs, Henan University, Kaifeng 475004, China. Electronic address: [email protected].
  • 7 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
PMID: 41352537 DOI: 10.1016/j.virs.2025.12.002
Abstract

Human Enterovirus A71 (EV-A71) is a major causative agent of hand, foot and mouth disease (HFMD), which poses a significant public health threat, particularly among young children. Mitochondrial Antiviral signaling protein (MAVS) and interferon regulatory factor 3 (IRF3) are vital proteins for the induction of type I interferons (IFN-I) and downstream interferon-stimulated genes (ISGs) during EV-A71 Infection. While posttranslational modifications are known to critically influence viral Infection processes, the mechanisms by which EV-A71 exploits host deubiquitinases (DUBs) for immune evasion remain poorly understood. In this study, we demonstrated that EV-A71 Infection upregulated Ubiquitin-Specific Protease 5 (USP5) expression. Knockdown of USP5 not only inhibited EV-A71 replication but also observably increased the production of IFN-I and ISGs. Furthermore, USP5 also regulated the replication of EV-D68 and CVA16 and the production of IFN-I and ISGs. Mechanistically, USP5 physically interacted with MAVS and IRF3 and reduced the K63-linked polyubiquitination of MAVS and IRF3. Conversely, USP5 knockdown increased the K63-linked polyubiquitination of MAVS and IRF3, thereby accelerating the phosphorylation of IRF3 and increasing IFN-I production during EV-A71 Infection. Furthermore, pharmacological inhibition of USP5 with the small-molecule inhibitor PR-619 significantly potentiated the Antiviral effects of IFN against EV-A71. Collectively, our findings reveal a previously unrecognized role of USP5 in facilitating EV-A71 immune evasion by dampening MAVS- and IRF3-mediated Antiviral signaling. These insights provide a novel therapeutic avenue for combating EV-A71 Infection through targeted modulation of the USP5-IRF3 axis.

Keywords

Enterovirus A71 (EV-A71); Innate immunity; Interferon regulatory factor 3 (IRF3); Mitochondrial antiviral signaling protein (MAVS); Ubiquitin-specific protease 5 (USP5).

Figures
Products
Inhibitors & Agonists
Other Products