2. Academic Validation
  3. Ubiquitin-specific protease 21 aggravates enterovirus 71 (EV71) infection by restricting Lys48-linked ubiquitination of EV71-2A protease

Ubiquitin-specific protease 21 aggravates enterovirus 71 (EV71) infection by restricting Lys48-linked ubiquitination of EV71-2A protease

  • Int J Biol Macromol. 2025 Jun:314:144202. doi: 10.1016/j.ijbiomac.2025.144202.
Xinyu Yang 1,  Mengyuan Tang 2,  Lichao Zang 3,  Panpan Hao 4,  Yan Chen 5,  Yukang Yuan 6,  Ying Miao 7,  Yibo Zuo 8,  Zhiyun Wu 9,  Zhiping Che 10,  Tengfei Ren 11,  Qiuyu Wu 12,  Yang Peng 13,  Wei Zhou 14,  Hui Zheng 15,  Weifeng Shi 16
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Department of Sperm Bank, Changhai Hospital, Naval Medical University (Second Military Medical University), 200433 Shanghai, China. Electronic address: yang1998xinyu@163.com.
  • 2 Department of Clinical Laboratory, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: mytang13@163.com.
  • 3 Department of Clinical Laboratory, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Department of Clinical Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo First Hospital, Ningbo, China. Electronic address: z1348134186@163.com.
  • 4 Department of Clinical Laboratory, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: 3129286170@qq.com.
  • 5 Department of Clinical Laboratory, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: CySweet1002@163.com.
  • 6 Department of Laboratory Medicine, Institute of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, 611731 Chengdu, Sichuan, China; Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215123, Jiangsu, China. Electronic address: yuanyukang1989@163.com.
  • 7 Department of Laboratory Medicine, Institute of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, 611731 Chengdu, Sichuan, China; Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215123, Jiangsu, China. Electronic address: yingm93@163.com.
  • 8 Department of Laboratory Medicine, Institute of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, 611731 Chengdu, Sichuan, China; Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215123, Jiangsu, China. Electronic address: yibo27@163.com.
  • 9 Department of Clinical Laboratory, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: zhiyunwu@126.com.
  • 10 Department of Clinical Laboratory, Changzhou Children's Hospital, Changzhou, Jiangsu 213003, China. Electronic address: Chezhiping1983@163.com.
  • 11 Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215123, Jiangsu, China. Electronic address: 172238517@qq.com.
  • 12 Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215123, Jiangsu, China. Electronic address: 15805379826@163.com.
  • 13 Department of Clinical Laboratory, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: pengyang1028@126.com.
  • 14 Department of Clinical Laboratory, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: weiz@suda.edu.cn.
  • 15 Department of Laboratory Medicine, Institute of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, 611731 Chengdu, Sichuan, China; Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215123, Jiangsu, China. Electronic address: huizheng@uestc.edu.cn.
  • 16 Department of Clinical Laboratory, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: swf1234@suda.edu.cn.
PMID: 40373892 DOI: 10.1016/j.ijbiomac.2025.144202
Abstract

EV71-encoded 2A protease (2Apro) plays an important regulatory role in EV71 Infection and replication. EV71-2Apro can help the viral immune escape by inhibiting host proteins, thereby disrupting the host Antiviral immune response. However, the mechanism by which 2Apro proteins are regulated in host cells remains largely unknown. In this study, we identified USP21 that promotes EV71 Infection. We discovered that USP21 downregulated K48-linked polyubiquitination of EV71-2Apro and stabilized 2Apro, ultimately promoting EV71 Infection. Furthermore, the small-molecule inhibitor, BAY-805, reduced 2Apro levels and inhibited EV71 Infection both in vivo and in vitro. Importantly, we found that the expression level of USP21 was positively correlated with the severity of EV71 Infection. This study reveals the crucial regulatory role of USP21 in EV71 Infection and provides a potential target for the treatment of EV71 Infection.

Keywords

2A(pro); BAY-805; Deubiquitination; EV71; USP21.

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