Usp5, short for ubiquitin-specific protease 5, is a crucial deubiquitinating enzyme. It regulates diverse physiological functions by removing ubiquitin chains from target proteins, thus influencing various cellular processes like cell proliferation, apoptosis, and DNA damage response. It is involved in multiple pathways and holds great biological importance in maintaining cellular homeostasis [4]. Genetic models, such as KO or CKO mouse models, have been instrumental in understanding its functions.

Conditional knockout of Usp5 in T cells increases the production of effector cytokines and retards tumor growth in mice, revealing its role in tumor immunotherapy through regulating PD-1 homeostasis [1]. Knockdown of Usp5 inhibits SLUG deubiquitination, suppressing HCC cells proliferation, metastasis, and invasion, indicating its role in promoting epithelial-mesenchymal transition in hepatocellular carcinoma [2]. In Kras-driven lung cancer development, knockout of Becn1 (downstream of USP5 activation) leads to increased senescence and reduced autophagy, suggesting the importance of the USP5-Beclin 1 axis in overriding p53-dependent senescence [3]. Knockdown of USP5 retards tumor growth in the Lewis lung carcinoma mouse model, as it is a regulator of PD-L1 stability in non-small cell lung cancer [5].

In conclusion, Usp5 plays essential roles in multiple biological processes and disease conditions. Studies using KO/CKO mouse models have significantly contributed to understanding its functions in areas like tumor immunotherapy, cancer cell metastasis, and cancer-associated senescence. These findings provide a basis for developing therapeutic strategies targeting Usp5 in relevant diseases.

References:

1. Xiao, Xiangling, Shi, Jie, He, Chuan, Xie, Conghua, Zhang, Jinfang. 2023. ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy. In Nature communications, 14, 2859. doi:10.1038/s41467-023-38605-3. https://pubmed.ncbi.nlm.nih.gov/37208329/

2. Meng, Jing, Ai, Xiaoyu, Lei, Yueyang, Sun, Tao, Yang, Cheng. 2019. USP5 promotes epithelial-mesenchymal transition by stabilizing SLUG in hepatocellular carcinoma. In Theranostics, 9, 573-587. doi:10.7150/thno.27654. https://pubmed.ncbi.nlm.nih.gov/30809294/

3. Li, Juan, Wang, Yang, Luo, Yue, Yuan, Junying, Xiao, Zhi-Xiong Jim. 2022. USP5-Beclin 1 axis overrides p53-dependent senescence and drives Kras-induced tumorigenicity. In Nature communications, 13, 7799. doi:10.1038/s41467-022-35557-y. https://pubmed.ncbi.nlm.nih.gov/36528652/

4. Gao, Si-Ting, Xin, Xin, Wang, Zhuo-Yuan, Hu, Yi-Yang, Feng, Qin. 2023. USP5: Comprehensive insights into structure, function, biological and disease-related implications, and emerging therapeutic opportunities. In Molecular and cellular probes, 73, 101944. doi:10.1016/j.mcp.2023.101944. https://pubmed.ncbi.nlm.nih.gov/38049041/

5. Pan, Jinghua, Qiao, Yiting, Chen, Congcong, Chen, Jianxiang, Chen, Guo. 2021. USP5 facilitates non-small cell lung cancer progression through stabilization of PD-L1. In Cell death & disease, 12, 1051. doi:10.1038/s41419-021-04356-6. https://pubmed.ncbi.nlm.nih.gov/34741014/