title: The Regulations of Deubiquitinase USP15 and Its Pathophysiological Mechanisms in Diseases.
abstract: 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.
authors.affiliation: Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 807, Taiwan. fatchou1988@hotmail.com.|Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. fatchou1988@hotmail.com.
authors.forename: Chon-Kit
authors.initials: CK
authors.lastname: Chou
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. c.jasmine8306@gmail.com.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Chang
authors.affiliation: Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 807, Taiwan. mickorinek@hotmail.com.|Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. mickorinek@hotmail.com.
authors.forename: Michal
authors.initials: M
authors.lastname: Korinek
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117, Singapore. mdccyt@nus.edu.sg.
authors.forename: Yei-Tsung
authors.initials: YT
authors.lastname: Chen
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. tinayang101@gmail.com.
authors.forename: Ya-Ting
authors.initials: YT
authors.lastname: Yang
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. st.leu.tw@gmail.com.|Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 807, Taiwan. st.leu.tw@gmail.com.
authors.forename: Steve
authors.initials: S
authors.lastname: Leu
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. linili@cc.kmu.edu.tw.
authors.forename: I-Ling
authors.initials: IL
authors.lastname: Lin
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. candace0602@gmail.com.
authors.forename: Chin-Ju
authors.initials: CJ
authors.lastname: Tang
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. cchiu@kmu.edu.tw.|Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. cchiu@kmu.edu.tw.|Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. cchiu@kmu.edu.tw.|Translational Research Center, Cancer Center and Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. cchiu@kmu.edu.tw.|Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan. cchiu@kmu.edu.tw.
authors.forename: Chien-Chih
authors.initials: CC
authors.lastname: Chiu
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002874:Chromosome Mapping; D004198:Disease Susceptibility; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D042541:Intracellular Space; D007527:Isoenzymes; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D064570:Ubiquitin-Specific Proteases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D007527:Isoenzymes; C579226:USP15 protein, human; D064570:Ubiquitin-Specific Proteases
keywords: IκBα; Parkinson’s disease; TGF-β; cancer-related signaling networks; deubiquitinase; ubiquitin-specific protease 15