ArticleNature chemical biology2025
Discovery and mechanism of K63-linkage-directed deubiquitinase activity in USP53.
Article in Nature chemical biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Mechanism of K63-linked polyubiquitin recognition and cleavage by the BRCA1-A complex.Nature communications · 2026Article
- Deubiquitinating enzymes in cervical cancer: Molecular mechanisms and therapeutic implications (Review).International journal of oncology · 2026Review
- Cathepsin L deletion enhances sensitivity to anticancer drugs through Parkin-mediated ubiquitination of Bcl-xL and USP53-induced Survivin destabilization.Cell death and differentiation · 2026Article
- Modulation of mitochondrial quality control in sepsis by traditional Chinese medicine: mechanistic insights and translational perspectives.Frontiers in pharmacology · 2026Review
- Use of a High-Affinity Ubiquitin-Binding Domain to Detect and Purify Ubiquitinated Substrates and Their Interacting Proteins.Bio-protocol · 2025Article
- Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30.Nature structural & molecular biology · 2025Article
- Small Molecule-Induced Alterations of Protein Polyubiquitination Revealed by Mass-Spectrometric Ubiquitome Analysis.Angewandte Chemie (International ed. in English) · 2025Article
- N-glycosylated LTβR increases the Th17/Treg cell ratio in liver cancer by blocking RORC ubiquitination and FOXP3 transcription.Cell death & disease · 2025Article
- Targeting USP22 to promote K63-linked ubiquitination and degradation of SARS-CoV-2 nucleocapsid protein.Journal of virology · 2025Article
- Light-Activatable Ubiquitin for Studying Linkage-Specific Ubiquitin Chain Formation Kinetics.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- USP53 Drives Ethanol-Induced Myocardial Injury by Promoting K63 Deubiquitination-Dependent RIPK1 Activation at K377.Research (Washington, D.C.) · 2025Article
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Authors and funding
11 authors.
Funding
Abstract
Ubiquitin-specific proteases (USPs) represent the largest class of human deubiquitinases (DUBs) and comprise its phylogenetically most distant members USP53 and USP54, which are annotated as catalytically inactive pseudoenzymes. Conspicuously, mutations within the USP domain of USP53 cause progressive familial intrahepatic cholestasis. Here, we report the discovery that USP53 and USP54 are active DUBs with high specificity for K63-linked polyubiquitin. We demonstrate how USP53 mutations abrogate catalytic activity, implicating loss of DUB activity in USP53-mediated pathology. Depletion of USP53 increases K63-linked ubiquitination of tricellular junction components. Assays with substrate-bound polyubiquitin reveal that USP54 cleaves within K63-linked chains, whereas USP53 can en bloc deubiquitinate substrate proteins in a K63-linkage-dependent manner. Biochemical and structural analyses uncover underlying K63-specific S2 ubiquitin-binding sites within their catalytic domains. Collectively, our work revises the annotation of USP53 and USP54, provides reagents and a mechanistic framework to investigate K63-linked polyubiquitin decoding and establishes K63-linkage-directed deubiquitination as a new DUB activity.
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