Ubiquitin carboxyl-terminal hydrolase L5 (UCHL5) (UCHL5)

Ubiquitin carboxyl-terminal hydrolase L5 (UCHL5), also known as UCH37, is a deubiquitinating enzyme (DUB) that plays a critical role in the ubiquitin-proteasome system (UPS). It is primarily associated with the 19S regulatory particle of the 26S proteasome, where it removes ubiquitin chains from substrates to facilitate their degradation. Beyond its role in the proteasome, UCHL5 is a component of the INO80 chromatin remodeling complex, influencing DNA repair and gene transcription. In various malignancies, including multiple myeloma and several solid tumors, UCHL5 is frequently overexpressed and correlates with poor clinical outcomes and treatment resistance. It promotes oncogenesis by stabilizing key signaling proteins in the Wnt/beta-catenin, Hedgehog, and TGF-beta pathways. Therapeutic targeting of UCHL5, often in conjunction with USP14, using small molecule inhibitors like VLX1570 and b-AP15, aims to disrupt protein homeostasis, leading to the accumulation of polyubiquitinated proteins and subsequent apoptosis in cancer cells.

Other names

UCH37Ubiquitin C-terminal hydrolase L5Ubiquitin carboxyl-terminal esterase L5Ubiquitin thioesterase L5CGI-92INO80 complex subunit R

Inhibition of deubiquitinating activity at the 19S proteasome regulatory particle, leading to the accumulation of polyubiquitinated proteins, induction of proteotoxic stress, and activation of apoptosis.