Background
The deubiquitylating enzymes (DUBs) regulate ubiquitin dependent signaling pathways. The activities of the DUBs are diverse and 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 protein (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. CYLD is a cytoplasmic deubiquitylating enzyme belonging to the Ubiquitin Carboxy-terminal Hydrolase (UCH) family and cloning of the gene was first described by Bignell et al. (2000). CYLD comprises a Cytoskeletal-Associated Protein-Glycine-conserved (CAP-GLY) domain, a proline rich region, an SH3 binding domain and a sequence homology to the catalytic domain of a UCH. CYLD has been identified as a tumour suppressor protein and negatively regulates the c-Jun NH(2)-terminal kinase (JNK) signalling pathway by inhibiting the activation of Map-Kinase Kinase7 (MKK7) (Reiley et al., 2004). CYLD is a negative regulator of the NF-kappaB (NFκB) signalling pathway by inhibiting the TNFR-Associated Factor 2 (TRAF2) mediated activation of IKappaB Kinase (IKK) (Kovalenko et al., 2003). Mutated CYLD is known to be associated with cylindromatosis, multiple familial trichoepithelioma, and Brooke-Spiegler syndrome (Hellerbrand et al., 2007; Trompouki et al., 2003).
References
Bignell GR, Warren W, et al. (2000) Identification of the familial cylindromatosis tumour-suppressor gene. Nat Genet 25, 160-5.
Hellerbrand C, Bumes E, Bataille F, Diemaier W, Massoumi R, Bosserhoff AK (2007) Reduced expression of CYLD in human colon and hepatocellular carcinomas. Carcinogenesis 28, 21-7.
Komander D, Clague MJ, Urbe S (2009) Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 10, 550-63.
Kovalenko A, Chable-Bessia C, Cantarella G, Israel A, Wallach D, Courtois G (2003) The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature 424, 801-5.
Reiley W, Zhang M, Sun SC (2004) Negative regulation of JNK signaling by the tumor suppressor CYLD. J Biol Chem 279, 55161-7.
Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer H, Ashworth A, Mosialos G (2003) CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature 424, 793-6.