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

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

  • Virol Sin. 2025 Sep 2:S1995-820X(25)00125-7. doi: 10.1016/j.virs.2025.08.004.
Chuntian Li 1,  Yuncheng Li 2,  Ranqing Cheng 2,  Miaomiao Li 2,  Mudan Zhang 3,  Zhiyuan Zhu 2,  Ping Yang 3,  Qinxue Hu 4,  Yalan Liu 5
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Henan University, School of Medicine, Henan University, Kaifeng, 475004, China.
  • 2 State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China.
  • 4 State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: qhu@wh.iov.cn.
  • 5 State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China; Hubei Jiangxia Laboratory, Wuhan, 430200, China. Electronic address: liuyl@wh.iov.cn.
PMID: 40907749 DOI: 10.1016/j.virs.2025.08.004
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.

Keywords

Glycoprotein B (gB); Herpes simplex virus 2 (HSV-2); UXT-V2; Ubiquitination.

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