Ubiquitously expressed transcript isoform 2 (UXT-V2) restricts HSV-2 replication by targeting glycoprotein B for degradation through ubiquitin-proteasome pathway

Chuntian Li; Yuncheng Li; Ranqing Cheng; Miaomiao Li; Mudan Zhang; Zhiyuan Zhu; Ping Yang; Qinxue Hu; Yalan Liu

doi:10.1016/j.virs.2025.08.004

October 2025

Chuntian Li, Yuncheng Li, Ranqing Cheng, Miaomiao Li, Mudan Zhang, Zhiyuan Zhu, Ping Yang, Qinxue Hu and Yalan Liu. Ubiquitously expressed transcript isoform 2 (UXT-V2) restricts HSV-2 replication by targeting glycoprotein B for degradation through ubiquitin-proteasome pathway[J]. Virologica Sinica, 2025, 40(5): 778-792. doi: 10.1016/j.virs.2025.08.004

Citation: Chuntian Li, Yuncheng Li, Ranqing Cheng, Miaomiao Li, Mudan Zhang, Zhiyuan Zhu, Ping Yang, Qinxue Hu, Yalan Liu. Ubiquitously expressed transcript isoform 2 (UXT-V2) restricts HSV-2 replication by targeting glycoprotein B for degradation through ubiquitin-proteasome pathway .VIROLOGICA SINICA, 2025, 40(5) : 778-792. http://dx.doi.org/10.1016/j.virs.2025.08.004

UXT-V2通过泛素-蛋白酶体途径降解gB限制HSV-2复制

李春天 ^a ,
李运程 ^b,c ,
程冉卿 ^b,c ,
李苗苗 ^b,c ,
章牡丹 ^b ,
朱智远 ^b,c ,
杨萍 ^b ,
胡勤学 ^b,c,, ,
刘雅兰 ^b,c,d,,

a 河南大学第一附属医院;
b. 中国科学院武汉病毒研究所, 高致病性病毒与生物安全全国重点实验室;
c. 中国科学院大学存济医学院d湖北江夏实验室

通讯作者： 胡勤学, qhu@wh.iov.cn; 刘雅兰, liuyl@wh.iov.cn
收稿日期： 2025-04-28
录用日期： 2025-08-27

摘要

单纯泡疹病毒2型（HSV-2）是导致新生儿疱疹的主要病原体，还会增加感染人类免疫缺陷病毒1型（HIV-1）的风险。然而，宿主限制HSV-2感染的机制尚未完全明确。广泛表达的转录异构体2（UXT-V2）是一种α型前折叠蛋白，作为多功能转录因子与多种人类肿瘤相关，但其在病毒感染中的作用仍不清楚。在本研究中，过表达UXT-V2能显著抑制HSV-2的复制，而敲除内源性表达的UXT-V2则会促进HSV-2的增殖。进一步分析表明，UXT-V2对HSV-2复制的限制作用与其调节NF-KB的功能无关。在HSV-2感染或gB转染的细胞中，UXT-V2促使gB发生K48连接的多聚泛素化，进而通过蛋白酶体途径使其降解，从而抑制病毒复制。此外还发现UXT-V2通过招募E3泛素连接酶TRIM21，促进gB的K48连接泛素化。反过来，HSV-2感染会降低体外培养细胞和小鼠体内UXT-V2蛋白的含量，这凸显了HSV-2与宿主相互作用的复杂性。综上所述，我们的研究首次证明了UXT-V2能拮抗HSV-2感染，揭示了一种宿主因子调节病毒糖蛋白稳态的新型免疫防御机制。
- 人类单纯疱疹病毒2型（HSV-2）
- , 泛素化表达转录本异构体2（UXT-V2）
- , 糖蛋白B（gB）
- , 泛素化

Ubiquitously expressed transcript isoform 2 (UXT-V2) restricts HSV-2 replication by targeting glycoprotein B for degradation through ubiquitin-proteasome pathway

Chuntian Li ^a ,
Yuncheng Li ^b,c ,
Ranqing Cheng ^b,c ,
Miaomiao Li ^b,c ,
Mudan Zhang ^b ,
Zhiyuan Zhu ^b,c ,
Ping Yang ^b ,
Qinxue Hu ^b,c,, ,
Yalan Liu ^b,c,d,,

a. Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Henan University, School of Medicine, Henan University, Kaifeng, 475004, China;
b. State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China;
c. Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China;
d. Hubei Jiangxia Laboratory, Wuhan, 430200, China

Corresponding author: Qinxue Hu, qhu@wh.iov.cn Yalan Liu, liuyl@wh.iov.cn
Received Date: 28 April 2025
Accepted Date: 27 August 2025

Abstract

Herpes simplex virus 2 (HSV-2) is a major pathogen causing neonatal herpes and increasing the risk of human immunodeficiency virus 1 (HIV-1) infection. However, the mechanisms underlying host restriction of HSV-2 infection are still not fully understood. The ubiquitously expressed transcript isoform 2 (UXT-V2), an α-type prefoldin protein, functions as a versatile transcription factor associated with numerous human tumors, but its role in viral infection remains unclear. In this study, we found that ectopic expression of UXT-V2 significantly inhibited HSV-2 replication, while knockout of endogenously expressed UXT-V2 promoted HSV-2 proliferation. Further analysis revealed that UXT-V2 restricts HSV-2 replication independent of its role in regulating NF-κB. In the context of HSV-2 infection or in viral glycoprotein B (gB)-transfected cells, UXT-V2 facilitates K48-linked ubiquitination of gB, leading to its degradation via the proteasome pathway, thereby inhibiting viral replication. Furthermore, we identified that UXT-V2 interacts with gB, recruiting the E3 ligase TRIM21 to facilitate K48-linked ubiquitination of gB. HSV-2, in turn, reduces the abundance of UXT-V2 proteins both in vitro and in mice, highlighting the complexity of HSV-2-host interactions. Collectively, our findings, for the first time, demonstrate an anti-HSV-2 role of UXT-V2, unveiling a novel host immune defense mechanism involved in regulating glycoprotein homeostasis.
- Herpes simplex virus 2 (HSV-2)
- , UXT-V2
- , Glycoprotein B (gB)
- , Ubiquitination

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