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4. Constitutive and induced forms of membrane-bound proteinase 3 interact with antineutrophil cytoplasmic antibodies and promote immune activation of neutrophils.

Author

Guarino, Carla, Seren, Seda, Lemoine, Roxane, Hummel, Amber M., Margotin, Jean-Edouard, El-Benna, Jamel, Hoarau, Cyrille, Specks, Ulrich, Jenne, Dieter E., and Korkmaz, Brice

Subjects
*ANTINEUTROPHIL cytoplasmic antibodies, *NEUTROPHILS, *PROTEINASES, *ELASTASES
Abstract

Proteinase 3 (PR3) is the main target antigen of antineutrophil cytoplasmic antibodies (ANCAs) in PR3-ANCA-associated vasculitis. A small fraction of PR3 is constitutively exposed on the surface of quiescent blood neutrophils in a proteolytically inactive form. When activated, neutrophils expose an induced form of membrane-bound PR3 (PR3mb) on their surface as well, which is enzymatically less active than unbound PR3 in solution due to its altered conformation. In this work, our objective was to understand the respective role of constitutive and induced PR3mb in the immune activation of neutrophils triggered by murine anti-PR3 mAbs and human PR3-ANCA. We quantified immune activation of neutrophils by the measurement of the production of superoxide anions and secreted protease activity in the cell supernatant before and after treatment of the cells by alpha-1 protease inhibitor that clears induced PR3mb from the cell surface. Incubation of TNFa-primed neutrophils with anti-PR3 antibodies resulted in a significant increase in superoxide anion production, membrane activation marker exposition, and secreted protease activity. When primed neutrophils were first treated with alpha-1 protease inhibitor, we observed a partial reduction in antibody-induced neutrophil activation, suggesting that constitutive PR3mb is sufficient to activate neutrophils. The pretreatment of primed neutrophils with purified antigenbinding fragments used as competitor significantly reduced cell activation by whole antibodies. This led us to the conclusion that PR3mb promoted immune activation of neutrophils. We propose that blocking and/or elimination of PR3mb offers a new therapeutic strategy to attenuate neutrophil activation in patients with PR3-ANCA-associated vasculitis. [ABSTRACT FROM AUTHOR]

Published
2023
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6. Exploiting the S4–S5 Specificity of Human Neutrophil Proteinase 3 to Improve the Potency of Peptidyl Di(chlorophenyl)-phosphonate Ester Inhibitors: A Kinetic and Molecular Modeling Analysis

Author

Guarino, Carla, Gruba, Natalia, Grzywa, Renata, Dyguda-Kazimierowicz, Edyta, Hamon, Yveline, Łȩgowska, Monika, Skoreński, Marcin, Dallet-Choisy, Sandrine, Marchand-Adam, Sylvain, Kellenberger, Christine, Jenne, Dieter E., Sieńczyk, Marcin, Lesner, Adam, Gauthier, Francis, and Korkmaz, Brice

Abstract

The neutrophilic serine protease proteinase 3 (PR3) is involved in inflammation and immune response and thus appears as a therapeutic target for a variety of infectious and inflammatory diseases. Here we combined kinetic and molecular docking studies to increase the potency of peptidyl-diphenyl phosphonate PR3 inhibitors. Occupancy of the S1 subsite of PR3 by a nVal residue and of the S4–S5 subsites by a biotinylated Val residue as obtained in biotin-VYDnVP(O-C6H4-4-Cl)2enhanced the second-order inhibition constant kobs/[I] toward PR3 by more than 10 times (kobs/[I] = 73000 ± 5000 M–1s–1) as compared to the best phosphonate PR3 inhibitor previously reported. This inhibitor shows no significant inhibitory activity toward human neutrophil elastase and resists proteolytic degradation in sputa from cystic fibrosis patients. It also inhibits macaque PR3 but not the PR3 from rodents and can thus be used for in vivo assays in a primate model of inflammation.

Published
2024
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7. Exploiting the S4–S5 Specificity of Human Neutrophil Proteinase 3 to Improve the Potency of Peptidyl Di(chlorophenyl)-phosphonate Ester Inhibitors: A Kinetic and Molecular Modeling Analysis

Author

Guarino, Carla, primary, Gruba, Natalia, additional, Grzywa, Renata, additional, Dyguda-Kazimierowicz, Edyta, additional, Hamon, Yveline, additional, Łȩgowska, Monika, additional, Skoreński, Marcin, additional, Dallet-Choisy, Sandrine, additional, Marchand-Adam, Sylvain, additional, Kellenberger, Christine, additional, Jenne, Dieter E., additional, Sieńczyk, Marcin, additional, Lesner, Adam, additional, Gauthier, Francis, additional, and Korkmaz, Brice, additional

Published
2018
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8. Prolonged pharmacological inhibition of cathepsin C results in elimination of neutrophil serine proteases

Author

Guarino, Carla, primary, Hamon, Yveline, additional, Croix, Cécile, additional, Lamort, Anne-Sophie, additional, Dallet-Choisy, Sandrine, additional, Marchand-Adam, Sylvain, additional, Lesner, Adam, additional, Baranek, Thomas, additional, Viaud-Massuard, Marie-Claude, additional, Lauritzen, Conni, additional, Pedersen, John, additional, Heuzé-Vourc'h, Nathalie, additional, Si-Tahar, Mustapha, additional, Fıratlı, Erhan, additional, Jenne, Dieter E., additional, Gauthier, Francis, additional, Horwitz, Marshall S., additional, Borregaard, Niels, additional, and Korkmaz, Brice, additional

Published
2017
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12. New Selective Peptidyl Di(chlorophenyl) Phosphonate Esters for Visualizing and Blocking Neutrophil Proteinase 3 in Human Diseases

Author

Guarino, Carla, primary, Legowska, Monika, additional, Epinette, Christophe, additional, Kellenberger, Christine, additional, Dallet-Choisy, Sandrine, additional, Sieńczyk, Marcin, additional, Gabant, Guillaume, additional, Cadene, Martine, additional, Zoidakis, Jérôme, additional, Vlahou, Antonia, additional, Wysocka, Magdalena, additional, Marchand-Adam, Sylvain, additional, Jenne, Dieter E., additional, Lesner, Adam, additional, Gauthier, Francis, additional, and Korkmaz, Brice, additional

Published
2014
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13. Regulation of Cell Polarity by Posttranslational Protein Palmitoylation.

Author

Chen B, Guarino C, Azzi A, Erb H, and Wu X

Subjects
Cysteine metabolism, Protein Processing, Post-Translational, Proteins metabolism, Cell Polarity, Lipoylation
Abstract

Cell polarity is a common feature of many living cells, especially epithelial cells, and plays important roles in development, tissue homeostasis, and diseases. Therefore, the signaling pathways involved in establishing and maintaining cell polarity are tightly controlled. Protein S-palmitoylation has been recently recognized as an important posttranslational modification involved in cell polarity, via dynamic covalent attachment of fatty acyl groups to the cysteine residues of cell polarity proteins. Here, we describe the methods to study the function and regulation of S-palmitoylation of cell polarity proteins., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

Published
2022
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