Deubiquitinating

Deubiquitinating, or deubiquitination, is the enzymatic removal of ubiquitin molecules from proteins. It is carried out by deubiquitinating enzymes (DUBs), a diverse family of proteases that reverse ubiquitination, thereby influencing protein stability, localization, and signaling. Ubiquitination attaches ubiquitin to substrates via E1, E2, and E3 enzymes, generating mono- or polyubiquitin chains that convey distinct cellular outcomes.

DUBs hydrolyze isopeptide bonds between ubiquitin and substrates or within ubiquitin chains, counteracting ubiquitination and recycling ubiquitin. They are organized into several families, including ubiquitin-specific proteases (USPs), ubiquitin C-terminal hydrolases (UCHs), ovarian tumor proteases (OTUs), Machado-Joseph disease proteases (MJDs), and JAMM/MPN+ metalloproteases. Most DUBs are cysteine proteases, while JAMMs are metalloproteases. DUBs show specificity for substrates and chain linkages, and their activity is influenced by localization and regulatory cofactors.

Biological roles of DUBs are diverse, spanning protein quality control, DNA repair, cell cycle progression, transcription, and immune signaling. By editing ubiquitin signals, they can prevent degradation, alter signaling pathways, or modulate protein activity. DUB function is highly context dependent, and dysregulation is linked to cancers, neurodegenerative diseases, and inflammatory conditions.

Research on deubiquitination uses genetics, biochemistry, and chemical biology. Tools include activity-based probes and selective inhibitors to study individual DUBs. Because DUBs sculpt ubiquitin landscapes, they are considered potential therapeutic targets for diseases where ubiquitin signaling is perturbed.