{Reference Type}: Journal Article
{Title}: Dipeptidyl peptidases and E3 ligases of N-degron pathways cooperate to regulate protein stability.
{Author}: Shimshon A;Dahan K;Israel-Gueta M;Olmayev-Yaakobov D;Timms RT;Bekturova A;Makaros Y;Elledge SJ;Koren I;
{Journal}: J Cell Biol
{Volume}: 223
{Issue}: 8
{Year}: 2024 Aug 5
{Factor}: 8.077
{DOI}: 10.1083/jcb.202311035
{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.