Ubiquitin carboxyl-terminal hydrolase isozyme L3 (UCH-L3) (UCH-L3)

Ubiquitin carboxyl-terminal hydrolase isozyme L3 (UCH-L3) is a deubiquitinating enzyme (DUB) belonging to the C-terminal hydrolase family that plays a critical role in maintaining cellular protein homeostasis. It functions by cleaving ubiquitin from precursor proteins and polyubiquitinated substrates, and it is uniquely capable of processing the ubiquitin-like protein NEDD8 to its mature form [1, 6, 10]. UCH-L3 is involved in diverse biological processes, including DNA damage repair (via stabilization of RAD51 and Ku80), cell cycle regulation, and glucose metabolism [1, 4, 7]. In oncology, it frequently acts as an oncogene by stabilizing various oncoproteins such as β-catenin, Snail, and the aryl hydrocarbon receptor (AhR), thereby promoting tumor growth, metastasis, and resistance to radiotherapy [1, 14]. However, its role is context-dependent, as it has been reported to act as a tumor suppressor in metastatic prostate cancer [5, 15]. Beyond cancer, UCH-L3 is implicated in neurodegenerative diseases through its ability to hydrolyze mutant ubiquitin (UBB+1) and is essential for the maintenance of retinal and germ cells [5, 10, 13]. Small molecule inhibitors like TCID have been developed for research to explore its potential as a therapeutic target, particularly for sensitizing aggressive tumors to standard treatments [1, 12, 14].

Other names

UCHL3Ubiquitin thioesterase L3Ubiquitin carboxyl-terminal esterase L3Testicular tissue protein Li 221

Inhibition of deubiquitinating and deneddylating activity, leading to the degradation of stabilized oncoproteins and sensitization of cells to DNA-damaging agents.