br A brief introduction to DUBs The reversal of ubiquitin
A brief introduction to DUBs The reversal of ubiquitin conjugation of targeted proteins relies on deubiquitinating Adox (DUBs), which catalytically cleave single Ub or poly-ubiquitin chains from proteins. The human genome encodes approximately 100 potential DUBs which can be classified into six families: ubiquitin-specific proteases (USPs), ubiquitin COOH-terminal hydrolases (UCHs), ovarian tumor proteases (OTUs), Josephins, the JAB1/MPN/MOV34 family (JAMMs) and motif interacting with Ub-containing novel DUB family (MINDYs) (Abdul Rehman et al., 2016). USPs, UCHs, OTUs, Josephins and the newly identified MINDYs families are thiol proteases, while the sixth family, JAMMs, comprises zinc metalloproteases (Ronau, Beckmann, & Hochstrasser, 2016). The mechanism of protein degradation mediated by ubiquitin has been well studied; meanwhile, there are growing evidences that reveal the non-proteolytic roles of ubiquitin modification. Deubiquitination counteracts the ubiquitin cascade, including inhibiting E2 ubiquitin conjugating enzymes and E3 ligases. Proteasome-related DUBs help to prevent degradation of proteins conjugated with an ubiquitin chain. Lysosome-associated DUBs play crucial roles in receptor degradation and recycling. Alternatively, DUBs can remove or edit ubiquitin chains to alter the signals mediated by non-degradation ubiquitin. After severing ubiquitin chains from proteins, DUBs also generate free ubiquitin from ubiquitin precursors and release ubiquitin from unanchored isopeptide-linked ubiquitin chains into the ubiquitin pool (Komander, Clague, & Urbé, 2009). Growing evidence indicates germline and somatic mutations, as well as alterations in expression frequency of DUBs, correlate with human disease, ranging from immune diseases to many human cancers. Mutations or deletions in DUBs could be involved in tumors. For example, the DUB A20 is a negative regulator of NF-κB pathway. Several studies have reported the deletions or mutations of TNFAIP3 (encoding gene of A20) in lymphomas such as the marginal zone lymphoma and the Non-Hodgkin's Lymphoma, indicating A20 is a tumor suppressor and/or immune regulator (Honma et al., 2009, Nocturne et al., 2013). Mutated A20 results in truncated proteins which are defective in inhibiting NF-κB pathway, leading to an increased expression of NF-κB-mediated proinflammatory cytokines (Zhou et al., 2016). Many DUBs are associated with tumors by their alterations in protein expression. For instance, increased expression levels of OTUD6B, UCH37, VCPIP1, USP7 and COPS5 are detected in various breast cancers (Luise et al., 2011). USP6 is considered to be an oncogenic protein and is overexpressed in primary aneurysmal bone cyst (ABC) and nodular fasciitis by chromosome translocation, and forms fusion proteins with CDH11, TRAP150, ZNF9, OMD, and COL1A1, which result in promoter swapping and transcriptional up-regulation (Oliveira et al., 2004). However, the roles of the DUBs are poles apart depending upon the different tumor types. In certain types of cancers, such as colon and thyroid cancers, the mRNA level of USP4 is elevated, whereas in lung cancer, the USP4 protein level is decreased (Gupta, Copeland, Gilbert, Jenkins, & Gray, 1993). USP4 has been suggested as an oncogene which could deubiquitinate and stabilize ARF-BP1, counteracting the function of E3 ligase of p53 (Zhang, Berger, Yang, & Lu, 2011). In lung cancer, USP4 was identified as a negative regulator of TNFα-mediated migration in lung cancer cells by deubiquitinating TRAF2 and TRAF6 (Xiao et al., 2012). In prostate carcinoma, USP2 protein is upregulated, whereas in colon cancer, USP2 expression is downregulated. In prostate cancer, USP2 is responsible to the stabilization of Fatty Acid Synthase (FAS), leading to the protection of tumor cell from apoptosis. While lower expression in colon cancer, how it works in colon cancer still remains unclear. (Graner et al., 2004, Priolo et al., 2006).