Fig. 1: The role and mechanism of USPs family.
From: Ubiquitin-specific proteases in inflammatory bowel disease-related signalling pathway regulation
During the ubiquitination process, the cysteine group of the ubiquitin-activating enzyme (E1) conjugates the C-terminal carboxyl group of ubiquitin to initiate ubiquitination with assumption of an ATP. Subsequently, the ubiquitin-conjugating enzyme (E2) binds to E1 and activated ubiquitin complex, catalysing the ubiquitin transfer from E1 to the active site of E2 through transesterification reaction. Then the ubiquitin-protein ligase (E3) establishes an isopeptide bond with C-terminal glycine on ubiquitin and lysine on substrate to form a ubiquitin-substrate complex. Ubiquitin can be conjugated by another ubiquitin to form a polyubiquitin chain via seven Lys residues (Lys6, 11, 27, 29, 33, 48 and 63) or Met1 by E1/E2/E3 recruitment. Once marked by a ubiquitin chain especially Lys48-linked chain, substrate tends to be degraded by proteasome. However, this process can be reversed by DUBs including multiple USPs. For example, CYLD can deubiquitinates Met1- and Lys63-linked polyubiquitin chains for signalling [29]; USP30, the only human USP that inserted in the outer mitochondrial membrane, deubiquitinates Lys6-linked di-ubiquitin for mitophagy [112]; USP8 deubiquitinates Lys11 for autophagy regulation [113]; USP19 deubiquitinates Lys27-linked polyubiquitination for innate immune responses [114]; USP9X is implicated to deubiquitinate Lys29-linked polyubiquitination [115]; USP16 deubiquitinates Lys33-linked polyubiquitination for signalling [40]; USP7 deubiquitinates Lys48-linked polyubiquitin chains for suppression of proteasomal degradation [45]. With specific USP domain, USPs can recognized the ubiquitin and catalyse the cleavage of polyubiquitin chains in the proximal, middle or distal linkage.
