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Feedback Regulation of Cathepsin C by the Propeptide Dipeptides of Granzymes A and B

Janja Božič, Iztok Dolenc

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.


Keywords


Cathepsin C; granzyme; HPLC; dipeptides; transferase activity; product inhibition

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DOI: http://dx.doi.org/10.17344/acsi.2019.5192

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Copyright (c) 2019 Janja Božič, Iztok Dolenc

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