Deubiquitylases From Genes to Organism

Abstract

Ubiquitylation is a major posttranslational modification that controls most complex aspects of cell physiology. It is reversed through the action of a large family of deubiquitylating enzymes (DUBs) that are emerging as attractive therapeutic targets for a number of disease conditions. Here, we provide a comprehensive analysis of the complement of human DUBs, indicating structural motifs, typical cellular copy numbers, and tissue expression profiles. We discuss the means by which specificity is achieved and how DUB activity may be regulated. Generically DUB catalytic activity may be used to 1) maintain free ubiquitin levels, 2) rescue proteins from ubiquitin-mediated degradation, and 3) control the dynamics of ubiquitin-mediated signaling events. Functional roles of individual DUBs from each of five subfamilies in specific cellular processes are highlighted with an emphasis on those linked to pathological conditions where the association is supported by whole organism models. We then specifically consider the role of DUBs associated with protein degradative machineries and the influence of specific DUBs upon expression of receptors and channels at the plasma membrane.

Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies

“…DUB activity measurements in chronic Usp9x KD cells or those with full genetic Usp9x disruption supported evidence of a role for Usp24 in that adaptation because these DUBs are closely related and because Usp24 expression or activity was increased in Usp9x-deficient cells. 18,25 Importantly, Usp24 KD was more effective in controlling both myeloma cell survival and Mcl-1 protein levels, suggesting that WP1130 activity against Mcl-1 is manifested through dual Usp9x/Usp24 inhibition. Indeed, we have accruing evidence that both DUBs are capable of Mcl-1 association, but the extent of the association may be controlled by more than recognition by the catalytic domain.…”

“…Usp24 bears a high degree of biochemical and sequence similarity to Usp9x. 18 Lysates from H929 and MM1.S chronic Usp9x KD cells showed increased Usp24 protein expression ( Figure 3D) when compared with control KD cells. To determine whether these changes were an artifact of Usp9x shRNAmediated KD, we assessed DUB activity and Usp24 expression in two colon cancer cell lines with full genetic disruption of the Usp9x gene.…”

Ubiquitin chain diversity at a glance

“…Importantly, ubiquitylation is a reversible modification, and linkages between ubiquitin molecules or ubiquitin and substrate proteins are hydrolyzed by deubiquitylating enzymes (DUBs) (Clague et al, 2013).…”

Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Pathological Cardiac Hypertrophy

“…In particular, the ubiquitin-specific protease (USP) family is the largest subclass among the 5 DUB subclasses, with the highest substrate specificity, 9 and exhibit diverse tissue-specific expression patterns, 10 representing an intriguing pool for drug discovery. 11 USPs are pivotally involved in DNA repair, endocytosis, immune response, and carcinogenesis 12 ; however, the role of the USPs in cardiac pathology remains almost unknown.…”