TY - JOUR
T1 - Dipeptidyl peptidases and E3 ligases of N-degron pathways cooperate to regulate protein stability
AU - Shimshon, Adi
AU - Dahan, Karin
AU - Israel-Gueta, Mor
AU - Olmayev-Yaakobov, Diana
AU - Timms, Richard T.
AU - Bekturova, Aizat
AU - Makaros, Yaara
AU - Elledge, Stephen J.
AU - Koren, Itay
N1 - Publisher Copyright:
© 2024 Shimshon et al.
PY - 2024/8/5
Y1 - 2024/8/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85196253626&partnerID=8YFLogxK
U2 - 10.1083/jcb.202311035
DO - 10.1083/jcb.202311035
M3 - Article
C2 - 38874443
AN - SCOPUS:85196253626
SN - 0021-9525
VL - 223
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 8
M1 - e202311035
ER -