Selective ubiquitination of drug-like small molecules by the ubiquitin ligase HUWE1

Barbara Orth, Pavel Pohl, Florian Aust, Yanlong Ji, Ayshwarya Seenivasan, Olexandr Dybkov, Xiaojun Julia Liang, Lars Bock, Florian Leidner, Sophie Levantovsky, Patrick Schardey, Pascal Sander, Nathanael J. Disch, Masanja L. Trautz, Athanasia Mizi, Argyris Papantonis, Christof Lenz, Helmut Grubmüller, Wieland Steinchen, Christian Behrends, Henning Urlaub, Matthias Gehringer and Sonja Lorenz ()
Additional contact information
Barbara Orth: Research Group ‘Ubiquitin Signaling Specificity’
Pavel Pohl: Research Group ‘Ubiquitin Signaling Specificity’
Florian Aust: Research Group ‘Ubiquitin Signaling Specificity’
Yanlong Ji: Research Group ‘Bioanalytical Mass Spectrometry’
Ayshwarya Seenivasan: Research Group ‘Ubiquitin Signaling Specificity’
Olexandr Dybkov: Research Group ‘Bioanalytical Mass Spectrometry’
Xiaojun Julia Liang: Eberhard Karls University Tübingen
Lars Bock: Max Planck Institute for Multidisciplinary Sciences, Department of Theoretical and Computational Biophysics
Florian Leidner: Max Planck Institute for Multidisciplinary Sciences, Department of Theoretical and Computational Biophysics
Sophie Levantovsky: Ludwig-Maximilians-University München
Patrick Schardey: Research Group ‘Ubiquitin Signaling Specificity’
Pascal Sander: Eberhard Karls University Tübingen
Nathanael J. Disch: Eberhard Karls University Tübingen
Masanja L. Trautz: Eberhard Karls University Tübingen
Athanasia Mizi: University Medical Center Göttingen
Argyris Papantonis: University Medical Center Göttingen
Christof Lenz: University Medical Center Göttingen
Helmut Grubmüller: Max Planck Institute for Multidisciplinary Sciences, Department of Theoretical and Computational Biophysics
Wieland Steinchen: Philipps University Marburg
Christian Behrends: Ludwig-Maximilians-University München
Henning Urlaub: Research Group ‘Bioanalytical Mass Spectrometry’
Matthias Gehringer: Eberhard Karls University Tübingen
Sonja Lorenz: Research Group ‘Ubiquitin Signaling Specificity’

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63442-x

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