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DPP8/9 are not Required to Cleave Most Proline-Containing Peptides.

ABSTRACT: Small molecule inhibitors of the intracellular serine peptidases DPP8 and DPP9 (DPP8/9) activate the NLRP1 and CARD8 inflammasomes, but the key DPP8/9 substrates have not yet been identified. DPP8/9 cleave after proline to remove N-terminal dipeptides from peptides or proteins, and studies using pseudo-peptide reporter substrates have suggested that these enzymes may play key roles in the catabolism of many proline-containing peptides generated by the proteasome. Here, we evaluated the degradation of a wide array of actual peptides in cell lysates, and discovered that DPP8/9 are not in fact involved in the processing of the vast majority of proline-containing peptides. Overall, these results indicate that DPP8/9 have a much more limited substrate scope than previously thought, and likely specifically cleave some critically important, but as yet unknown, intracellular peptide or protein that regulates inflammasome activation.

SUBMITTER: Bhattacharjee A

PROVIDER: S-EPMC10655806 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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DPP8/9 are not Required to Cleave Most Proline-Containing Peptides.

Bhattacharjee Abir A Bachovchin Daniel A DA

Israel journal of chemistry 20230214 3-4

Small molecule inhibitors of the intracellular serine peptidases DPP8 and DPP9 (DPP8/9) activate the NLRP1 and CARD8 inflammasomes, but the key DPP8/9 substrates have not yet been identified. DPP8/9 cleave after proline to remove N-terminal dipeptides from peptides or proteins, and studies using pseudo-peptide reporter substrates have suggested that these enzymes may play key roles in the catabolism of many proline-containing peptides generated by the proteasome. Here, we evaluated the degradati ...[more]

PMID: 37982048

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