USP14

USP14, or ubiquitin-specific protease 14, is a member of the ubiquitin-specific protease (USP) family of deubiquitinating enzymes. In humans it is encoded by the USP14 gene and is conserved across eukaryotes. USP14 associates with the proteasome, binding to the 19S regulatory particle of the 26S proteasome, where it acts as a proteasome-associated deubiquitinase.

At the proteasome, USP14 cleaves ubiquitin from substrates as they are targeted for degradation, thereby editing ubiquitin chains and, in some cases, rescuing substrates from degradation. It also contributes to maintaining cellular free ubiquitin pools by hydrolyzing polyubiquitin chains to generate monomeric ubiquitin.

Regulation is influenced by proteasome binding; USP14 activity can slow degradation by trimming ubiquitin chains. Pharmacological inhibition of USP14, using compounds such as IU1 and related derivatives, reduces its deubiquitinase activity and has been shown to enhance proteasome-mediated degradation of certain ubiquitinated proteins in cells, assisting clearance of some misfolded or aggregation-prone proteins. This has spurred interest in USP14 as a therapeutic target in neurodegenerative diseases and cancer, with research focusing on selective inhibitors and their effects on proteostasis.

Structural features include a catalytic USP domain responsible for deubiquitination and regions that mediate proteasome association. The enzyme's activity relies on the conserved cysteine protease mechanism typical of USPs. USP14 expression is widespread, reflecting its role in maintaining ubiquitin homeostasis and protein turnover.