Feedback regulation of cathepsin C by the propeptide dipeptides of granzymes A and B

Abstract

Granzymes A and B are activated by proteolytic removal of their N-terminal dipeptides by cathepsin C (dipeptidyl-peptidase I). However, the possible physiological role of the cleaved dipeptides Glu-Lys and Gly-Glu is not yet understood. In this study, adding either of the two dipeptides to NK-92 cells, resulted in enhanced cytotoxicity toward the targeted K562 cells and increased death rate of the target cells. Cathepsin C is known to generate cytotoxic polymers from various dipeptides, however, in the case of the dipeptides Glu-Lys and Gly-Glu, cathepsin C was unable to polymerize them. Unexpectedly the dipeptides were found to be inhibitors of the transferase activity of cathepsin C (IC50 < 20 mM), and weak competitive inhibitors of the peptidase activity with Ki values in the millimolar range. This suggests that the dipeptides can play role in a feedback loop that controls transferase and proteolytic activities of cathepsin C in various biological processes.