ArticleNature communications2025
Selective ubiquitination of drug-like small molecules by the ubiquitin ligase HUWE1.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
What it found
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Who cites it
7 citing papers in PubMed.
- Article
- Ubiquitin beyond the proteome: lipids, glycans, metabolites, nucleic acids, and an expanding molecular landscape.Biochemical Society transactions · 2026Review
- Article
- HECT-type ubiquitin ligases: Emerging principles in the era of full-length structures.The Journal of biological chemistry · 2026Review
- Ubiquitin System-Driven Proteostasis in DNA Damage Response.International journal of molecular sciences · 2026Review
- Lysine deficiency within a conserved lysine desert is critical for EEL-1/HUWE1 to support ubiquitin proteasome system function.bioRxiv : the preprint server for biology · 2025Article
- The Ubiquitin Script: writing protein fates in chains.Essays in biochemistry · 2025Review
Corrections and comments
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Authors and funding
23 authors.
Funding
Abstract
The ubiquitin system regulates eukaryotic physiology by modifying myriad substrate proteins. Substrate specificity and the assembly of ubiquitin signals are determined by ubiquitin ligases, some of which also modify non-protein biomolecules. Here we expand this substrate realm, revealing that the human ligase HUWE1 can target drug-like small molecules. We demonstrate that compounds previously reported as HUWE1 inhibitors present substrates of their target ligase. Compound ubiquitination is driven by the canonical catalytic cascade, linking ubiquitin to the compound's primary amino group. In vitro, the modification is selectively catalyzed by HUWE1, allowing the compounds to compete with protein substrates. We establish cellular detection methods, confirming HUWE1 promotes - but does not exclusively drive - compound ubiquitination in cells. Converting the existing compounds into specific HUWE1 substrates or inhibitors thus requires enhanced specificity. More broadly, our findings open avenues for harnessing the ubiquitin system to transform exogenous small molecules into novel chemical modalities within cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.