Deubiquitinating enzymes and the proteasome regulate preferential sets of ubiquitin substrates

Fredrik Trulsson, Vyacheslav Akimov, Mihaela Robu, Nila van Overbeek, David Aureliano Pérez Berrocal, Rashmi G Shah, Jürgen Cox, Girish M Shah, Blagoy Blagoev*, Alfred C O Vertegaal

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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The ubiquitin-proteasome axis has been extensively explored at a system-wide level, but the impact of deubiquitinating enzymes (DUBs) on the ubiquitinome remains largely unknown. Here, we compare the contributions of the proteasome and DUBs on the global ubiquitinome, using UbiSite technology, inhibitors and mass spectrometry. We uncover large dynamic ubiquitin signalling networks with substrates and sites preferentially regulated by DUBs or by the proteasome, highlighting the role of DUBs in degradation-independent ubiquitination. DUBs regulate substrates via at least 40,000 unique sites. Regulated networks of ubiquitin substrates are involved in autophagy, apoptosis, genome integrity, telomere integrity, cell cycle progression, mitochondrial function, vesicle transport, signal transduction, transcription, pre-mRNA splicing and many other cellular processes. Moreover, we show that ubiquitin conjugated to SUMO2/3 forms a strong proteasomal degradation signal. Interestingly, PARP1 is hyper-ubiquitinated in response to DUB inhibition, which increases its enzymatic activity. Our study uncovers key regulatory roles of DUBs and provides a resource of endogenous ubiquitination sites to aid the analysis of substrate specific ubiquitin signalling.

Original languageEnglish
Article number2736
JournalNature Communications
Number of pages17
Publication statusPublished - 18. May 2022


  • Cell Division
  • Deubiquitinating Enzymes/metabolism
  • Proteasome Endopeptidase Complex/metabolism
  • Ubiquitin/metabolism
  • Ubiquitination


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