UCHL3

UCHL3 (ubiquitin carboxyl-terminal hydrolase L3) is a cysteine protease within the ubiquitin C-terminal hydrolase family that functions as a deubiquitinating enzyme and deNEDDylating enzyme, thereby regulating cellular ubiquitin homeostasis and post-translational protein modification pathways^[1][2]. Mechanistically, UCHL3 processes ubiquitin precursors and ubiquitinated substrates and hydrolyzes C-terminal glycine-linked ubiquitin or NEDD8 conjugates, linking its activity to protein turnover, cell cycle regulation, DNA repair, apoptosis, and cellular stress responses^[1][2][3]. Through these functions, UCHL3 contributes to genome maintenance and proteostasis, and dysregulation of UCHL3 has been associated with cancer, neurodegenerative disorders, retinal degeneration, and learning deficits in experimental models^[1][2]. In disease-related pathways, UCHL3 can stabilize signaling components through deubiquitination and has been implicated in DNA damage repair mechanisms, further supporting its relevance as a therapeutic research target^[2][4][5]. Compared with the closely related isoform UCHL1, UCHL3 shares approximately 53% sequence homology but exhibits distinct biochemical characteristics and biological functions, highlighting the importance of isoform-specific investigation in ubiquitin signaling studies^[2]. Structural studies further identified a catalytic cysteine protease core and a substrate-selectivity crossover loop that contribute to UCHL3 substrate recognition and enzymatic specificity^[5][6]. For experimental applications, increasing interest has focused on the development of UCHL3 inhibitors to interrogate its roles in DNA repair, protein homeostasis, and disease-associated signaling networks^[2][4].