Journal Article

The Regulations of Deubiquitinase USP15 and Its Pathophysiological Mechanisms in Diseases

Yei Tsung Chen, Steve Leu, Chin-Ju Tang, Michal Korinek, Chien-Chih Chiu, I-Ling Lin, Ya-Ting Yang, Chon-Kit Chou, Yu-Ting Chang

2017

Overview

Deubiquitinases (DUBs) play a critical role in ubiquitin-directed signaling by catalytically removing the ubiquitin from substrate proteins. Ubiquitin-specific protease 15 (USP15), a member of the largest subfamily of cysteine protease DUBs, contains two conservative cysteine (Cys) and histidine (His) boxes. USP15 harbors two zinc-binding motifs that are essential for recognition of poly-ubiquitin chains. USP15 is grouped into the same category with USP4 and USP11 due to high degree of homology in an N-terminal region consisting of domains present in ubiquitin-specific proteases (DUSP) domain and ubiquitin-like (UBL) domain. USP15 cooperates with COP9 signalosome complex (CSN) to maintain the stability of cullin-ring ligase (CRL) adaptor proteins by removing the conjugated ubiquitin chains from RBX1 subunit of CRL. USP15 is also implicated in the stabilization of the human papillomavirus type 16 E6 oncoprotein, adenomatous polyposis coli, and IκBα. Recently, reports have suggested that USP15 acts as a key regulator of TGF-β receptor-signaling pathways by deubiquitinating the TGF-β receptor itself and its downstream transducers receptor-regulated SMADs (R-SMADs), including SMAD1, SMAD2, and SMAD3, thus activating the TGF-β target genes. Although the importance of USP15 in pathologic processes remains ambiguous so far, in this review, we endeavor to summarize the literature regarding the relationship of the deubiquitinating action of USP15 with the proteins involved in the regulation of Parkinson’s disease, virus infection, and cancer-related signaling networks.

• Publisher: MDPI AG,MDPI
• Subject: animal / Animals / beta catenin / cell transformation / Cell Transformation, Neoplastic / Cell Transformation, Neoplastic - genetics / Cell Transformation, Neoplastic - metabolism / chemistry / chromosomal mapping / Chromosome Mapping / COP9 signalosome / cullin / cysteine / deubiquitinase / disease predisposition / Disease Susceptibility / drug resistance / Drug Resistance, Neoplasm / Drug Resistance, Neoplasm - genetics / enzyme activity / enzyme regulation / Gene Expression / Gene Expression Regulation / gene location / genetic transcription / histidine / human / Humans / immunoglobulin enhancer binding protein / innate immunity / Intracellular Space / isoenzyme / Isoenzymes / messenger RNA / molecular pathology / nonhuman / nuclear export signal / nuclear localization signal / nuclear magnetic resonance spectroscopy / Papillomaviridae / Parkinson disease / Protein Binding / protein domain / protein E6 / protein expression / Protein Interaction Domains and Motifs / protein MDM2 / protein p53 / protein stability / Protein Transport / Review / Signal Transduction / Smad protein / Structure-Activity Relationship / transforming growth factor beta / transforming growth factor beta receptor / tripartite motif protein / ubiquitin protein ligase / ubiquitin specific protease 11 / ubiquitin specific protease 15 / ubiquitin specific protease 4 / Ubiquitin-Specific Proteases / Ubiquitin-Specific Proteases - chemistry / Ubiquitin-Specific Proteases - genetics / Ubiquitin-Specific Proteases - metabolism / Ubiquitination / unclassified drug / USP15 protein / virus infection