Discovery of USP53 and USP54 deubiquitinase activities
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Date
2025
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Abstract
Deubiquitinating enzymes (DUBs) are proteases that cleave isopeptide bonds in between ubiquitin chains or between ubiquitin and substrates. Thereby, they determine the final ubiquitination status of substrates regulating their activity, localization, stability or cellular function. USP53 and USP54 are classified as DUBs but have previously been reported to be catalytically inactive. Both have been associated with cancer, and USP53 with cholestasis and hearing loss. However, a molecular understanding of their activities, functions, and disease association remains elusive. In this study, the catalytic activity of USP53 and USP54 was investigated by expression and purification of the catalytic domains, followed by biochemical and structural characterization. The results of this study establish USP53 and USP54 as active DUBs with distinct molecular mechanisms for the length-dependent decoding of K63-linked ubiquitin chains and will guide the analysis of their cellular functions. In addition, loss of USP53 activity was identified as a likely cause of the observed cholestasis phenotype, highlighting the importance of the catalytic activity of DUBs in the context of disease.
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Keywords
Deubiquitinase, DUB, USP53, USP54, Activity, Crystallography
Subjects based on RSWK
Proteasen, Ubiquitin