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.
Highlights
The balance of ubiquitin conjugation and de-conjugation is a well-tuned mechanism dictating the intracellular fate of the substrate proteins
The current study suggested that the cooperation between CSN and Ubiquitin-specific protease 15 (USP15) is implicated in negative regulation of Wnt signaling by supporting the build-up of β-catenin destruction complex, which is composed of axin, casein kinase 1α, and glycogen synthase kinase 3β and requires adenomatous polyposis coli (APC) to recruit phosphorylated β-catenin
Inappropriate ubiquitin modification is often associated with diseases, such as Parkinson’s disease, virus infections, and certain types of cancer, the particular ubiquitin-modified protein substrates could be used to study the biological significance of ubiquitin ligases or DUBs
Summary
The balance of ubiquitin conjugation and de-conjugation is a well-tuned mechanism dictating the intracellular fate of the substrate proteins. In order to use the tagged form of ubiquitin for protein destruction, the poly-ubiquitin chain is linked together via Lys-48 residue persuading substrate proteins to undergo 26S proteasomal degradation [5]. Deubiquitination is important for processing of precursor ubiquitin into its mature form, because the mature ubiquitin is capable of conjugating with protein substrates via its exposed C-terminus. Proteins possessing the tumor-suppressing function have been identified as substrates for USP15 deubiquitination, including p53, an inhibitor of NF-κB (IκBα) and adenomatous polyposis coli (APC). We review how the USP15 domains function in deubiquitination of protein substrates, and comprehensively describe the connection between USP15 and signaling pathways associated with cancer and other diseases
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