DUBs

Deubiquitinating enzymes (DUBs) are proteases that remove ubiquitin molecules from proteins or edit polyubiquitin chains. By reversing ubiquitination, they regulate protein stability, localization, and activity, and they shape numerous cellular processes including proteostasis, cell cycle progression, DNA damage response, and immune signaling. DUBs counteract ubiquitin ligases and can determine whether a substrate is degraded by the proteasome or participates in signaling pathways.

Most DUBs are cysteine proteases belonging to several families, such as ubiquitin-specific proteases (USPs), ubiquitin C-terminal hydrolases (UCHs), ovarian tumor domain proteases (OTUs), and Josephin domain-containing DUBs. A distinct group is the JAMM/JAB1/MPN domain metalloproteases, which are zinc-dependent enzymes. These metalloproteases include members such as AMSH and AMSH-LP. DUBs can function alone or as components of larger protein complexes.

DUBs exhibit varying specificity for ubiquitin linkages and chain topology. Some broadly remove ubiquitin from substrates, while others preferentially cleave specific linkages (for example, K48, K63, or linear Met1-linked chains). By editing chain length and topology, DUBs influence whether a protein is degraded, participates in signaling cascades, or is trafficked within the cell.

DUB activity is implicated in numerous diseases, including cancer, neurodegenerative disorders, and inflammatory conditions. As a result, DUBs are investigated as therapeutic targets, with inhibitors or modulators in development aimed at restoring proper ubiquitin signaling. Well-known DUBs include CYLD, OTULIN, USP7, and A20 (TNFAIP3), illustrating the diversity of substrates and functions within this enzyme family.