Deubiquitinase

Deubiquitinases (DUBs) are enzymes that remove ubiquitin from proteins or detach ubiquitin chains. By reversing ubiquitination, DUBs regulate protein stability, localization, and activity, influencing processes such as proteasomal degradation, signaling, DNA repair, and endocytosis.

DUBs fall into two broad catalytic classes: cysteine proteases (including ubiquitin-specific proteases USPs/UBPs, OTU domain proteases, and MJD family) and metalloproteases of the JAMM/MPN+ family (for example Rpn11/PSMD14, a proteasome subunit). They hydrolyze isopeptide bonds between ubiquitin and substrates or within ubiquitin chains. Some DUBs show preference for particular ubiquitin linkages, such as K48 or K63, or for linear chains.

Functionally, DUBs can rescue substrates from degradation by removing degradative signals, generate free ubiquitin by processing precursor ubiquitin, and shape chain architectures to regulate signaling, DNA damage response, trafficking, and autophagy. DUB activity is controlled by localization, cofactors, post-translational modifications, and allosteric regulation.

Notable examples include USP7 (HAUSP), which regulates p53 pathway components; CYLD, a negative regulator of NF-κB signaling; USP14 and UCHL5, which associate with the proteasome; OTUB1; and BRCC36 and AMSH, which participate in DNA repair and endosomal sorting.

DUBs are explored as therapeutic targets; dysregulation is linked to cancer, neurodegeneration, and immune disorders. Small-molecule inhibitors and modulators have been developed for several DUBs, with ongoing efforts to achieve selectivity and to map cellular networks. Research approaches include activity-based probes, structural biology, and genome editing.