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

Area of Science:

• Biochemistry
• Immunology
• Molecular Biology

Background:

• Dipeptidyl peptidases 8 and 9 (DPP8/9) are intracellular serine peptidases.
• Inhibition of DPP8/9 activates the NLRP1 and CARD8 inflammasomes.
• The specific substrates of DPP8/9 remain unidentified.

Purpose of the Study:

• To identify the key substrates of DPP8/9.
• To investigate the role of DPP8/9 in inflammasome activation pathways.
• To determine the substrate scope of DPP8/9 in cellular environments.

Main Methods:

• Evaluation of the degradation of various actual peptides in cell lysates.
• Analysis of DPP8/9 enzymatic activity on proline-containing peptides.
• Assessment of the impact of DPP8/9 inhibition on inflammasome activation.

Main Results:

• DPP8/9 were found not to be involved in the processing of most proline-containing peptides.
• The substrate scope of DPP8/9 is significantly narrower than previously suggested by pseudo-peptide reporter studies.
• DPP8/9 likely cleave specific, yet unidentified, intracellular peptides or proteins regulating inflammasome activation.

Conclusions:

• DPP8/9 have a limited substrate specificity.
• The previously assumed broad role of DPP8/9 in proline-peptide catabolism is inaccurate.
• Further research is needed to identify the specific substrates of DPP8/9 crucial for inflammasome regulation.