Deubiquitinaser

Deubiquitinases (DUBs) are enzymes that remove ubiquitin molecules from substrate proteins, counteracting ubiquitination by E3 ligases. By editing ubiquitin chains, they regulate protein stability, localization, and activity, influencing numerous cellular processes. DUBs function within the ubiquitin–proteasome system and help recycle ubiquitin.

DUBs are divided into several families. The largest group comprises cysteine proteases, including ubiquitin-specific proteases (USPs), ubiquitin C-terminal hydrolases (UCHs), OTU deubiquitinases, and Machado–Joseph disease proteases (MJD). A separate metalloprotease family, JAMM/MPN+, uses zinc for catalysis. DUBs vary in substrate and linkage specificity, allowing fine-tuned regulation of ubiquitin signals.

Mechanistically, DUBs employ an active-site cysteine (cysteine proteases) or a zinc-dependent catalytic center (JAMM/MPN+) to cleave the isopeptide bond linking ubiquitin to substrate or to another ubiquitin. They can edit chain length and linkage type, rescue substrates from degradation, or modulate signaling pathways, providing nuanced control over protein fate and activity.

Biological roles are diverse, including regulation of protein turnover, DNA repair, transcription, signal transduction, endocytosis, and autophagy. DUB activity helps maintain cellular ubiquitin pools and shapes immune responses. Dysregulation of DUBs has been linked to cancer, neurodegenerative diseases, and infectious disorders, highlighting their importance in health and disease.

Because of their central role, DUBs are attractive therapeutic targets. Inhibitors and modulators for several DUBs, such as USP7 and USP14, are in preclinical or clinical development, reflecting ongoing efforts to exploit deubiquitination in disease treatment.