Vcpip1, also known as valosin-containing protein-interacting protein 1, is a deubiquitinating enzyme. It plays essential roles in multiple biological processes. It is involved in post-mitotic Golgi cisternae reassembly and maintenance in interphase by interacting with P97/VCP, forming a complex that promotes Golgi membrane fusion [1]. Vcpip1 is also implicated in DNA repair, as it deubiquitinates SPRTN in response to DNA-protein crosslinks (DPCs), promoting SPRTN's chromatin relocalization and subsequent acetylation, which is crucial for DPC repair and maintaining genomic stability [5].

In macrophages, Vcpip1 deficiency reduces Erbin expression, increases NF-κB phosphorylation, and promotes the release of inflammatory factors (IL-1β, IL-6, and TNF-α), indicating its role in negatively regulating NF-κB signaling pathways [2]. In the context of hepatitis B virus (HBV) infection, Vcpip1 directly binds to HBV regulatory protein X (HBx), stabilizes HBx by reducing its proteasomal degradation, and upregulates HBV transcription, antigen expression, and genome replication. It also positively modulates HBV enhancer I/X promoter activities, establishing it as a multi-functional positive regulator of HBV [3,4].

In conclusion, Vcpip1 is a key deubiquitinating enzyme involved in diverse biological functions such as organelle assembly, DNA repair, and immune-related signaling pathways. Its role in HBV-related diseases and inflammatory responses, as revealed through functional studies including those with potential genetic models, highlights its importance in understanding these disease mechanisms, which may provide new directions for therapeutic strategies.

References:

1. Liao, Tianzhui, Li, Ruotong, Lu, Ping, Gao, Haishan, Li, Faxiang. 2024. Molecular Basis of VCPIP1 and P97/VCP Interaction Reveals Its Functions in Post-Mitotic Golgi Reassembly. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2403417. doi:10.1002/advs.202403417. https://pubmed.ncbi.nlm.nih.gov/39234822/

2. Zuo, Jing, Wu, Die, Zhang, Ying, Wu, Xiaojing, Song, Xuemin. 2024. VCPIP1 negatively regulates NF-κB signaling pathways by deubiquitinating and stabilizing Erbin in MDP-stimulated macrophages. In International immunopharmacology, 143, 113622. doi:10.1016/j.intimp.2024.113622. https://pubmed.ncbi.nlm.nih.gov/39550842/

3. Kang, Ning, Liu, Nannan, Liu, Mu, Shen, Zhongliang, Liu, Jing. 2024. Identification and characterization of host factor VCPIP1 as a multi-functional positive regulator of hepatitis B virus. In Journal of virology, 98, e0158124. doi:10.1128/jvi.01581-24. https://pubmed.ncbi.nlm.nih.gov/39494904/

4. Wu, Qiong, Zhang, Lu, Xu, Xiazhen, Lin, Xu, Chen, Wannan. 2022. Hepatitis B Virus X Protein Is Stabilized by the Deubiquitinating Enzyme VCPIP1 in a Ubiquitin-Independent Manner by Recruiting the 26S Proteasome Subunit PSMC3. In Journal of virology, 96, e0061122. doi:10.1128/jvi.00611-22. https://pubmed.ncbi.nlm.nih.gov/35695579/

5. Huang, Jinzhou, Zhou, Qin, Gao, Ming, Machida, Yuichi, Lou, Zhenkun. 2020. Tandem Deubiquitination and Acetylation of SPRTN Promotes DNA-Protein Crosslink Repair and Protects against Aging. In Molecular cell, 79, 824-835.e5. doi:10.1016/j.molcel.2020.06.027. https://pubmed.ncbi.nlm.nih.gov/32649882/