Ubiquitin-specific peptidase 14 (USP14) (USP14)

Ubiquitin-specific peptidase 14 (USP14) is a major deubiquitinating enzyme (DUB) that reversibly associates with the 19S regulatory particle of the 26S proteasome. It exerts a dual function in regulating protein degradation: it can protect substrates from degradation by removing ubiquitin chains or promote degradation by allosterically activating the proteasome. USP14 is involved in key signaling pathways such as Wnt/beta-catenin and NF-kappaB, and it regulates the stability of proteins like Tau, alpha-synuclein, and fatty acid synthase (FASN). Overexpression of USP14 is linked to various cancers, including neuroblastoma and colorectal cancer, where it promotes cell proliferation and survival. In neurodegenerative diseases, USP14 inhibition has been shown to enhance the degradation of toxic protein aggregates. Small-molecule inhibitors like IU1 and b-AP15 have been developed to target USP14, though clinical progress has been hampered by challenges such as the lung toxicity observed with the inhibitor VLX1570.

Other names

Ubiquitin-specific protease 14TGTUbp6Ubiquitin carboxyl-terminal hydrolase 14

USP14 inhibitors typically act by binding to the catalytic site or allosterically modulating the enzyme to prevent the removal of ubiquitin chains from substrates. This inhibition can either enhance the degradation of specific proteasomal substrates by preventing premature deubiquitination (as seen with IU1) or induce proteotoxic stress and apoptosis by blocking the recycling of ubiquitin and causing the accumulation of polyubiquitinated proteins (as seen with b-AP15).