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 specific protease 9, X chromosome (USP9X) is a member of the cysteine protease enzyme family and cloning of the human gene was first described by Jones et al. (1996). USP9X is a deubiquitylase involved both in the processing of many different ubiquitin precursors and ubiquitylated proteins. USP9X is known to stabilise β-catenin, thereby enhancing pro-survival Notch and WNT signalling, as well as the self-renewal of embryonic stem cell-derived neural progenitors. USP9X also enhances transforming growth factor-β (TGF-β) signalling via deubiquitylation of TGF-β receptors and SMAD intracellular mediators (Vucic et al., 2011). USP9X acts by removing monoubiquitin from SMAD4, thereby permitting its association with phospho-SMAD2 and subsequent activation of TGF-β/SMAD-responsive gene targets. USP9X has also been shown to control AMP-activated protein kinase (AMPK)-related kinase activity through direct removal of non-canonical K29 and/or K33-linked ubiquitin chains (Sacco et al., 2010). USP9X can also stabilise levels of myeloid cell leukemia sequence 1 protein (MCL1) and thereby promotes cell survival. USP9X binds MCL1 and removes the Lys 48-linked polyubiquitin chains that normally mark MCL1 for proteasomal degradation. Increased USP9X expression correlates with increased MCL1 protein in human follicular lymphomas and diffuse large B-cell lymphomas. Moreover, patients with multiple myeloma overexpressing USP9X have a poor prognosis. These results identify USP9X as a prognostic and therapeutic target, and they show that deubiquitylases may stabilise labile oncoproteins in human malignancies (Schwickart et al., 2010). USP9X also interacts and deubiquitylates α-synuclein in vitro and in vivo. α-Synuclein is central to the pathogenesis of Parkinson disease (PD). Drugs that modulate USP9X activity, together with enhancers of autophagy or proteasomal activity, may help decrease the levels of α-synuclein and provide a novel therapeutic strategy to treat α-synucleinopathies (Rott et al., 2011)
References
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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.
Rott R, Szargel R, Haskin J, Bandopadhyay R, Lees AJ, Shani V, Engelender S (2011) alpha-Synuclein fate is determined by USP9X-regulated monoubiquitination. Proc Nat Acad Sci USA 108, 18666-18671.
Sacco JJ, Coulson JM, Clague MJ, Urbe S (2010) Emerging roles of deubiquitinases in cancer-associated pathways. IUBMB Life 62, 140-157.
Schwickart M, Huang X, Lill JR, Liu J, Ferrando R, French DM, Maecker H, O'Rourke K, Bazan F, Eastham-Anderson J, Yue P, Dornan D, Huang DC, Dixit VM (2010) Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature 463, 103-107.
Vucic D, Dixit VM, Wertz IE (2011) Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death. Nat Rev Mol Cell Biol 12, 439-452.