Dipeptidyl peptidases and E3 ligases of N-degron pathways cooperate to regulate protein stability

Adi Shimshon, Karin Dahan, Mor Israel-Gueta, Diana Olmayev-Yaakobov, Richard T. Timms, Aizat Bekturova, Yaara Makaros, Stephen J. Elledge, Itay Koren

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

N-degrons are short sequences located at protein N-terminus that mediate the interaction of E3 ligases (E3s) with substrates to promote their proteolysis. It is well established that N-degrons can be exposed following protease cleavage to allow recognition by E3s. However, our knowledge regarding how proteases and E3s cooperate in protein quality control mechanisms remains minimal. Using a systematic approach to monitor the protein stability of an N-terminome library, we found that proline residue at the third N-terminal position (hereafter “P+3”) promotes instability. Genetic perturbations identified the dipeptidyl peptidases DPP8 and DPP9 and the primary E3s of N-degron pathways, UBR proteins, as regulators of P+3 bearing substrate turnover. Interestingly, P+3 UBR substrates are significantly enriched for secretory proteins. We found that secretory proteins relying on a signal peptide (SP) for their targeting contain a “built-in” N-degron within their SP. This degron becomes exposed by DPP8/9 upon translocation failure to the designated compartments, thus enabling clearance of mislocalized proteins by UBRs to maintain proteostasis.

Original languageEnglish
Article numbere202311035
JournalJournal of Cell Biology
Volume223
Issue number8
DOIs
StatePublished - 5 Aug 2024
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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