Deubiquitylating enzyme (DUB)

Deubiquitylating enzymes (DUBs) are a large superfamily of approximately 100 proteases in humans that regulate the ubiquitin-proteasome system by cleaving ubiquitin from substrate proteins. By reversing the action of E3 ubiquitin ligases, DUBs play a pivotal role in maintaining protein homeostasis, regulating protein stability, and recycling free ubiquitin within the cell. They are classified into several distinct families, primarily cysteine proteases (such as USPs, UCHs, OTUs, and MJDs) and metalloproteases (JAMMs). DUBs are involved in critical biological processes including cell cycle progression, DNA repair, and various signaling pathways like NF-κB and Wnt. Their dysregulation is frequently associated with diseases such as cancer, where they may stabilize oncoproteins or degrade tumor suppressors, and neurodegenerative disorders, where they affect the clearance of misfolded proteins. Consequently, DUBs have emerged as attractive therapeutic targets, with several small-molecule inhibitors, particularly those targeting USP1 and USP7, currently in various stages of preclinical and clinical development.

Other names

Deubiquitinating enzymeDeubiquitinaseUbiquitin proteaseUbiquitin hydrolaseUbiquitin isopeptidaseDeubiquitylating peptidase

Inhibition of deubiquitinating activity to promote the degradation of specific oncoproteins or stabilize tumor suppressors by preventing the removal of degradative ubiquitin chains.