USPsUBPs

USPs and UBPs refer to a family of enzymes known as ubiquitin-specific proteases, a major class of deubiquitinating enzymes (DUBs) that remove ubiquitin from substrate proteins. In yeast, they are typically called ubiquitin-specific proteases (UBPs), while in humans and other higher eukaryotes the family is usually designated as USPs (ubiquitin-specific proteases). Despite naming differences, the two terms describe closely related enzymes that regulate protein turnover and signaling by editing ubiquitin chains.

These enzymes share a catalytic core known as the UBP domain, which contains a conserved active-site cysteine and histidine (and often an aspartate) that form a catalytic triad. They can be highly specific for particular ubiquitin linkages (such as K48- or K63-linked chains) or broader in scope, and many also remove ubiquitin from internal lysines within substrates. In addition to the catalytic domain, USPs/UBPs frequently feature regulatory regions that determine substrate recognition, localization, and interaction with other proteins, enabling diverse cellular functions.

USPs/UBPs play essential roles in numerous cellular processes, including protein quality control, DNA damage response, transcription, and signaling pathways. Notable human examples include USP7 (HAUSP), which influences p53 signaling by modulating MDM2, and USP1, which deubiquitinates PCNA during the DNA damage response. Because DUB activity shapes protein stability and activity, the USP/UBP family has attracted attention as a potential target for therapeutic intervention, particularly in cancer and viral infections. Several inhibitors have been described, but achieving high specificity remains challenging due to the conserved nature of the catalytic active site across DUBs.

In summary, USPs/UBPs constitute a conserved family of deubiquitinating enzymes that regulate ubiquitin signaling and protein fate, with diverse biological roles and ongoing relevance to disease research and drug discovery.