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. OTULIN is a cysteine protease and a member of the OTU (ovarian tumour) superfamily of proteins (Balakirev et al., 2003). Cloning of the human gene was first described by Ota et al. (2004). OTU enzymes play important roles as negative-feedback regulators in NF-kB signalling, interferon signalling and in p97 (cdc48)-mediated processes although the cellular functions of most OTU enzymes remain to be discovered. 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). OTULIN (OTU DUB with linear linkage specificity) is the latest OTU to be discovered. It has been proven to specifically cleave linear ubiquitin and antagonize the E3 ligase LUBAC (linear ubiquitin chain assembly complex), thereby regulating NF-κB signalling (Wiener and Wolberger, 2013). It has been shown that the overexpression of OTULIN prevents tumour necrosis factor a (TNFα)-induced NEMO (NFκB Essential Modifier) association with ubiquitylated RIPK1, suggesting that OTULIN regulates linear poly-ubiquitin signalling (Fiil et al., 2013; Keusekotten et al., 2013).
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