USP4, short for Ubiquitin-specific protease 4, is a deubiquitinating enzyme belonging to the largest subfamily of cysteine protease DUBs. It removes monoubiquitinated and polyubiquitinated chains from target proteins. USP4 is involved in multiple cellular processes and is tightly regulated under normal conditions. Aberrant expression or activity of USP4 is associated with various pathologies, especially cancers. Genetic models, such as gene knockout (KO) mouse models, are valuable for studying its functions [2].

In an ESCC nude mouse model, USP4 silencing inhibited tumor growth and metastasis, suggesting that USP4 promotes the proliferation, migration, and invasion of esophageal squamous cell carcinoma cells via the MEK/ERK signaling pathway [1]. In periodontitis, USP4 depletion-driven RAB7A ubiquitylation impairs autophagosome-lysosome fusion, and upregulation of USP4 could attenuate periodontitis in vivo [3]. In hepatic ischaemia/reperfusion injury, USP4 knockout mice exhibited exacerbated injury, with enhanced liver inflammation via the NF-κB signaling pathway and increased hepatocyte apoptosis, indicating that USP4 deficiency promotes activation of the TAK1/JNK signalling pathways [4].

In conclusion, USP4 plays crucial roles in multiple biological processes and diseases. Model-based research, especially KO mouse models, has revealed its significant contributions in cancer progression, periodontitis, and hepatic ischaemia/reperfusion injury. Understanding USP4's functions provides potential therapeutic targets for these disease areas.

References:

1. Zhang, Hongdian, Han, Youming, Xiao, Wanyi, Tang, Peng, Yu, Zhentao. 2023. USP4 promotes the proliferation, migration, and invasion of esophageal squamous cell carcinoma by targeting TAK1. In Cell death & disease, 14, 730. doi:10.1038/s41419-023-06259-0. https://pubmed.ncbi.nlm.nih.gov/37949874/

2. Hu, Binbin, Zhang, Dingyue, Zhao, Kejia, Fu, Qianmei, Ma, Xuelei. 2021. Spotlight on USP4: Structure, Function, and Regulation. In Frontiers in cell and developmental biology, 9, 595159. doi:10.3389/fcell.2021.595159. https://pubmed.ncbi.nlm.nih.gov/33681193/

3. Kang, Sen, Liu, Shuxin, Dong, Xian, Wang, Huiming, Ding, Pei-Hui. 2024. USP4 depletion-driven RAB7A ubiquitylation impairs autophagosome-lysosome fusion and aggravates periodontitis. In Autophagy, 21, 771-788. doi:10.1080/15548627.2024.2429371. https://pubmed.ncbi.nlm.nih.gov/39663592/

4. Zhou, Jiangqiao, Qiu, Tao, Wang, Tianyu, Zhang, Long, Zou, Jilin. 2019. USP4 deficiency exacerbates hepatic ischaemia/reperfusion injury via TAK1 signalling. In Clinical science (London, England : 1979), 133, 335-349. doi:10.1042/CS20180959. https://pubmed.ncbi.nlm.nih.gov/30622220/