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

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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
JournalJournal of Cell Biology
Issue number8
StatePublished - 5 Aug 2024

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© 2024 Shimshon et al.


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