Usp5, or ubiquitin-specific protease 5, is a deubiquitinase that plays a crucial role in regulating protein stability by removing ubiquitin chains from target proteins. It is involved in multiple cellular pathways, including those related to tumor-immune regulation, epithelial-mesenchymal transition, and autophagy [1-5]. Ubiquitination is a key post-translational modification process, and Usp5's function in deubiquitination has significant implications for various biological processes and disease states. Gene knockout (KO) and conditional knockout (CKO) mouse models are valuable tools for studying Usp5's function in vivo.

In T-cell conditional knockout of Usp5, it was found that this led to increased production of effector cytokines and retarded tumor growth in mice, suggesting that Usp5 has a role in modulating tumor immunotherapy by regulating PD-1 homeostasis. Mechanistically, USP5 interacts with PD-1, deubiquitinates and stabilizes it, and ERK phosphorylation promotes their interaction [1]. In hepatocellular carcinoma, knockdown of Usp5 in cell models and in a xenograft nude mouse model inhibited cell proliferation, metastasis, and invasion as it destabilized SLUG, which is involved in epithelial-mesenchymal transition [2]. In the context of Kras-induced lung cancer, knockout of Becn1 (downstream of Usp5 activation) in KrasG12D mice led to increased senescence and reduced autophagy, retarding lung tumor growth [3].

In conclusion, Usp5 is a vital deubiquitinase involved in multiple biological processes, especially those related to tumorigenesis and immune regulation. Studies using KO and CKO mouse models have significantly contributed to our understanding of Usp5's role in diseases such as cancer, highlighting its potential as a therapeutic target.