Ubiquitin-specific protease 15 (USP15)

Ubiquitin-specific protease 15 (USP15) is a cysteine protease belonging to the deubiquitinating enzyme (DUB) family, which plays a critical role in maintaining protein homeostasis by reversing the ubiquitination process (UniProt Q9Y4E8). It is a key regulator of the TGF-beta signaling pathway, where it deubiquitinates and stabilizes the TGF-beta type I receptor and SMAD proteins, thereby promoting oncogenic signaling in cancers such as glioblastoma and breast carcinoma (PMID: 22343894). Beyond cancer, USP15 is involved in diverse biological processes, including the regulation of the COP9 signalosome, mRNA splicing, and the innate immune response through the modulation of NF-kappaB and Type I interferon signaling (PMID: 25153103). As a therapeutic target, USP15 is of significant interest because its inhibition can lead to the degradation of key oncoproteins and the suppression of pro-tumorigenic pathways (PMID: 30655535). However, drug development is complicated by the high sequence identity USP15 shares with its paralogs USP4 and USP11, necessitating the design of highly selective small molecules to avoid off-target toxicities (PMID: 27085480).

Other names

Ubiquitin carboxyl-terminal hydrolase 15Deubiquitinating enzyme 15UnpELUSP15

Inhibition of deubiquitinating activity to promote the proteasomal degradation of substrate proteins