Ubiquitin-independent proteasomal degradation driven by C-degron pathways

Yaara Makaros, Anat Raiff, Richard T. Timms, Ajay R. Wagh, Mor Israel Gueta, Aizat Bekturova, Julia Guez-Haddad, Sagie Brodsky, Yarden Opatowsky, Michael H. Glickman, Stephen J. Elledge, Itay Koren

Research output: Contribution to journalArticlepeer-review


Although most eukaryotic proteins are targeted for proteasomal degradation by ubiquitination, a subset have been demonstrated to undergo ubiquitin-independent proteasomal degradation (UbInPD). However, little is known about the molecular mechanisms driving UbInPD and the degrons involved. Utilizing the GPS-peptidome approach, a systematic method for degron discovery, we found thousands of sequences that promote UbInPD; thus, UbInPD is more prevalent than currently appreciated. Furthermore, mutagenesis experiments revealed specific C-terminal degrons required for UbInPD. Stability profiling of a genome-wide collection of human open reading frames identified 69 full-length proteins subject to UbInPD. These included REC8 and CDCA4, proteins which control proliferation and survival, as well as mislocalized secretory proteins, suggesting that UbInPD performs both regulatory and protein quality control functions. In the context of full-length proteins, C termini also play a role in promoting UbInPD. Finally, we found that Ubiquilin family proteins mediate the proteasomal targeting of a subset of UbInPD substrates.

Original languageEnglish
Pages (from-to)1921-1935
JournalMolecular Cell
Issue number11
StatePublished - 1 Jun 2023


  • C-degron
  • Global Protein Stability (GPS) technology
  • Ubiquilin
  • Ubiquitin
  • degron
  • proteasome
  • ubiquitin-independent degradation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology


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