Pharmacological inhibition of cathepsin S and of NSPs-AAP-1 (a novel, alternative protease driving the activation of neutrophil serine proteases)

Domain, R.; Seren, S.; Jerke, U.; Makridakis, M.; Chen, K.J.; Zoidakis, J.; Rhimi, M.; Zhang, X.; Bonvent, T.; Croix, C.; Gonzalez, L.; Li, D.; Basso, J.; Paget, C.; Viaud-Massuard, M.C.; Lalmanach, G.; Shi, G.P.; Aghdassi, A.; Vlahou, A.; McDonald, P.P.; Couillin, I.; Williams, R.; Kettritz, R.; Korkmaz, B.

Pharmacological inhibition of cathepsin S and of NSPs-AAP-1 (a novel, alternative protease driving the activation of neutrophil serine proteases)

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Item Type:	Article
Title:	Pharmacological inhibition of cathepsin S and of NSPs-AAP-1 (a novel, alternative protease driving the activation of neutrophil serine proteases)
Creators Name:	Domain, R., Seren, S., Jerke, U., Makridakis, M., Chen, K.J., Zoidakis, J., Rhimi, M., Zhang, X., Bonvent, T., Croix, C., Gonzalez, L., Li, D., Basso, J., Paget, C., Viaud-Massuard, M.C., Lalmanach, G., Shi, G.P., Aghdassi, A., Vlahou, A., McDonald, P.P., Couillin, I., Williams, R., Kettritz, R. and Korkmaz, B.
Abstract:	An uncontrolled activity of neutrophil serine proteases (NSPs) contributes to inflammatory diseases. Cathepsin C (CatC) is known to activate NSPs during neutrophilic differentiation and represents a promising pharmacological target in NSP-mediated diseases. In humans, Papillon-Lefèvre syndrome (PLS) patients have mutations in their CTSC gene, resulting in the complete absence of CatC activity. Despite this, low residual NSP activities are detected in PLS neutrophils (<10% vs healthy individuals), suggesting the involvement of CatC-independent proteolytic pathway(s) in the activation of proNSPs. This prompted us to characterize CatC-independent NSP activation pathways by blocking proCatC maturation. In this study, we show that inhibition of intracellular CatS almost completely blocked CatC maturation in human promyeloid HL-60 cells. Despite this, NSP activation was not significantly reduced, confirming the presence of a CatC-independent activation pathway involving a CatC-like protease that we termed NSPs-AAP-1. Similarly, when human CD34+ progenitor cells were treated with CatS inhibitors during neutrophilic differentiation in vitro, CatC activity was nearly abrogated but ∼30% NSP activities remained, further supporting the existence of NSPs-AAP-1. Our data indicate that NSPs-AAP-1 is a cysteine protease that is inhibited by reversible nitrile compounds designed for CatC inhibition. We further established a proof of concept for the indirect, although incomplete, inhibition of NSPs by pharmacological targeting of CatC maturation using CatS inhibitors. This emphasizes the potential of CatS as a therapeutic target for inflammatory diseases. Thus, preventing proNSP maturation using a CatS inhibitor, alone or in combination with a CatC/NSPs-AAP-1 inhibitor, represents a promising approach to efficiently control the extent of tissue injury in neutrophil-mediated inflammatory diseases.
Keywords:	Cathepsin C, Cysteine Cathepsin, Neutrophil Serine Protease, Zymogen, Synthetic Inhibitor, Therapeutic Approach, Animals, Mice
Source:	Biochemical Pharmacology
ISSN:	0006-2952
Publisher:	Elsevier
Volume:	229
Page Range:	116114
Number of Pages:	1
Date:	November 2024
Official Publication:	https://doi.org/10.1016/j.bcp.2024.116114
PubMed:	View item in PubMed

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