Deconjugating enzymes (DCEs) are proteases that process ubiquitin or ubiquitin-like gene products, reverse the modification of proteins by a single ubiquitin or ubiquitin-like protein (UBL) and remodel polyubiquitin (or poly-UBL) chains on target proteins (Reyes-Turcu et al., 2009). The deubiquitylating - or deubiquitinating - enzymes (DUBs) represent the largest family of DCEs and regulate ubiquitin-dependent signalling pathways. The activities of the DUBs include the generation of free ubiquitin from precursor molecules, the recycling of ubiquitin following substrate degradation to maintain cellular ubiquitin homeostasis and the removal of ubiquitin or ubiquitin-like proteins (UBL) modifications through chain editing to rescue proteins from proteasomal degradation or to influence cell signalling events (Komander et al., 2009). There are two main classes of DUB, cysteine proteases and metalloproteases. OTUD5 is a cysteine protease and is a member of the OTU (ovarian tumour) superfamily of proteins (Balakirev et al., 2003). Cloning of the human gene was first described by Kayagaki et al. (2007). Ovarian tumour family DUBs contain a papain-like catalytic core of ~180 amino acids. In addition to their catalytic domain, many OTU members have additional ubiquitin-binding domains (UBDs). At least 20 different UBD families have been described, and knowledge of linkage-specific UBDs have provided the means to understand the roles of different ubiquitin linkages in cells (Licchesi et al., 2012). OTUD5 has been shown to selectively cleave K63–linked polyubiquitin chains on tumour necrosis factor receptor–associated factor 3 (TRAF3); an E3 ubiquitin ligase that preferentially assembles K63–linked polyubiquitin chains. Removal of these K63 polyubiquitin chains from TRAF3 results in its dissociation from the downstream signalling complex containing TANK binding kinase 1 (TBK1) (Kayagaki et al., 2007). Phosphorylation of OTUD5 at a single residue, Ser177, is both necessary and sufficient to activate the enzyme. A network of interactions involving the phosphate and the C-terminal tail of ubiquitin cause OTUD5 to fold around its substrate, revealing why phosphorylation is essential for deubiquitylase activity. Phosphoactivation of OTUD5 represents an unprecedented mode of protease regulation and a clear link between two major cellular signal transduction systems: phosphorylation and ubiquitin modification (Huang et al., 2012).
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