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.

Keywords: IκBα; Parkinson’s disease; TGF-β; cancer-related signaling networks; deubiquitinase; ubiquitin-specific protease 15.

Figure 1

Schematic illustration of the domain organization of human USP15. Catalytic core (shown in cyan) is located in the carboxyl-terminal portion of USP15. The catalytic core of USP15 contains an inserted UBL domain. The USP15 with its active triad C269, H862, and D879 are denoted by thick red lines, and the Zn-coordinating Cys residues in positions 419, 422, 780, and 783 are highlighted by thick black lines. Four residues (Met-122, Phe-123, Val-124, and His-126) interacting with SART3 located between the amino-terminal DUSP domain and UBL domain are indicated. DUSP, domain present in ubiquitin-specific proteases; UBL, ubiquitin-like fold.

Figure 2

Alignments of USP15 and its paralogs USP4 and USP11. Paralogs of USP15, USP4 (NP_003354.2), and USP11 (NP_004642.2), show high similarity and identity in domain structure with USP15 proteins. Overall, USP15 shares 57% identity with USP4, and 43.2% identity with USP11. DUSP, domain present in ubiquitin-specific proteases; UBL, ubiquitin-like fold; red color represents USP catalytic domain; Sim, protein sequence similarity.

Figure 3

USP15 acts as a “biological thermostat” in the TGF-β signaling pathway. USP15 competes with the action of SMAD7-SMURF2 complex that trends to promote the ubiquitination of type-1 TGF-β receptor. USP15 participates in deubiquitination of the monomeric ubiquitin from R-SMADs, which participates in transcription of TGF-β target genes. Protein ubiquitination is indicated by the presence of an attached ubiquitin moiety (Ub). The phosphate group (P) is shown as a red sphere.