Background
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 signaling 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. Ubiquitin carboxyl-terminal hydrolase L5 (UCHL5) is a member of the cysteine protease enzyme family and cloning of the human gene was first described by Wicks et al. (2005). The deubiquitylating activity of the proteasome has been attributed to the action of three deubiquitylases: UCHL5, USP14 and RPN11, which are all localised in the 19S regulatory particle. It has been reported that loss of both UCHL5 and USP14 leads to the accumulation of polyubiquitylated proteins and an inhibition of protein degradation without altering the structure or catalytic properties of the proteasome (D'Arcy et al., 2011). UCHL5 has been reported to interact with the inhibitory protein SMAD7 by regulating transforming growth factor-β (TGF-β) receptor ubiquitylation, stability and transcription (Sacco et al., 2010). The disruption of components in the TGF-β signalling cascade is a common occurrence in human cancers (Fang et al., 2010). The activity of UCHL5 (and UCHL3) has been shown to be upregulated in the majority of tumour tissues compared to the adjacent normal tissues pointing to a specific role of these enzymes in the regulation of cell function and proliferation in different conditions, lending further support to the idea that UCHL5 (plus other deubiquitylases such as USP7 and USP9X) may constitute an interesting new target for the development of anticancer drugs (Rolen et al., 2006)
References
D'Arcy P, Brnjic S, Olofsson MH, Fryknas M, Lindsten K, De Cesare M, Perego P, Sadeghi B, Hassan M, Larsson R, Linder S (2011) Inhibition of proteasome deubiquitinating activity as a new cancer therapy. Nat Med 17, 1636-1640.
Fang Y, Fu D, Shen XZ (2010) The potential role of ubiquitin c-terminal hydrolases in oncogenesis. Biochim Biophys Acta 1806, 1-6.
Komander D, Clague MJ, Urbe S (2009) Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 10, 550-563.
Reyes-Turcu FE, Ventii KH, Wilkinson KD (2009) Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Ann Rev Biochem 78, 363-397.
Rolen U, Kobzeva V, Gasparjan N, Ovaa H, Winberg G, Kisseljov F, Masucci MG (2006) Activity profiling of deubiquitinating enzymes in cervical carcinoma biopsies and cell lines. Mol Carcinog 45, 260-269.
Sacco JJ, Coulson JM, Clague MJ, Urbe S (2010) Emerging roles of deubiquitinases in cancer-associated pathways. IUBMB Life 62, 140-157.
Wicks SJ, Haros K, Maillard M, Song L, Cohen RE, Dijke PT, Chantry A (2005) The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-beta signalling. Oncogene 24, 8080-8084.