Ectodomain shedding of PLA2R1 is mediated by the metalloproteases ADAM10 and ADAM17.

Autor:	Dolla G; Centre National de la Recherche Scientifique, Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Université Côte d'Azur (UniCa), Valbonne, France., Nicolas S; Centre National de la Recherche Scientifique, Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Université Côte d'Azur (UniCa), Valbonne, France., Dos Santos LR; Centre National de la Recherche Scientifique, Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, Laboratoire d'Excellence DistALZ, Sophia Antipolis, Université Côte d'Azur (UniCa), Valbonne, France., Bourgeois A; Centre National de la Recherche Scientifique, Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, Laboratoire d'Excellence DistALZ, Sophia Antipolis, Université Côte d'Azur (UniCa), Valbonne, France., Pardossi-Piquard R; Centre National de la Recherche Scientifique, Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, Laboratoire d'Excellence DistALZ, Sophia Antipolis, Université Côte d'Azur (UniCa), Valbonne, France., Bihl F; Centre National de la Recherche Scientifique, Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Université Côte d'Azur (UniCa), Valbonne, France., Zaghrini C; Centre National de la Recherche Scientifique, Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Université Côte d'Azur (UniCa), Valbonne, France., Justino J; Centre National de la Recherche Scientifique, Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Université Côte d'Azur (UniCa), Valbonne, France., Payré C; Centre National de la Recherche Scientifique, Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Université Côte d'Azur (UniCa), Valbonne, France., Mansuelle P; Plateforme de Protéomique de l'Institut de Microbiologie de la Méditerranée (IMM), Marseille Protéomique (MaP), Aix Marseille Université (AMU), Centre National de la Recherche Scientifique (CNRS) FR3479, Marseille, France., Garbers C; Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany., Ronco P; Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S1155, Paris, France; Sorbonne Université, Université Pierre et Marie Curie Paris 06, Paris, France., Checler F; Centre National de la Recherche Scientifique, Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, Laboratoire d'Excellence DistALZ, Sophia Antipolis, Université Côte d'Azur (UniCa), Valbonne, France., Lambeau G; Centre National de la Recherche Scientifique, Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Université Côte d'Azur (UniCa), Valbonne, France. Electronic address: lambeau@ipmc.cnrs.fr., Petit-Paitel A; Centre National de la Recherche Scientifique, Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Université Côte d'Azur (UniCa), Valbonne, France. Electronic address: apetit@ipmc.cnrs.fr.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2024 Jul; Vol. 300 (7), pp. 107480. Date of Electronic Publication: 2024 Jun 17.
DOI:	10.1016/j.jbc.2024.107480
Abstrakt:	Phospholipase A2 receptor 1 (PLA2R1) is a 180-kDa transmembrane protein that plays a role in inflammation and cancer and is the major autoantigen in membranous nephropathy, a rare but severe autoimmune kidney disease. A soluble form of PLA2R1 has been detected in mouse and human serum. It is likely produced by proteolytic shedding of membrane-bound PLA2R1 but the mechanism is unknown. Here, we show that human PLA2R1 is cleaved by A Disintegrin And Metalloprotease 10 (ADAM10) and ADAM17 in HEK293 cells, mouse embryonic fibroblasts, and human podocytes. By combining site-directed mutagenesis and sequencing, we determined the exact cleavage site within the extracellular juxtamembrane stalk of human PLA2R1. Orthologs and paralogs of PLA2R1 are also shed. By using pharmacological inhibitors and genetic approaches with RNA interference and knock-out cellular models, we identified a major role of ADAM10 in the constitutive shedding of PLA2R1 and a dual role of ADAM10 and ADAM17 in the stimulated shedding. We did not observe evidence for cleavage by β- or γ-secretase, suggesting that PLA2R1 may not be a substrate for regulated intramembrane proteolysis. PLA2R1 shedding occurs constitutively and can be triggered by the calcium ionophore ionomycin, the protein kinase C activator PMA, cytokines, and lipopolysaccharides, in vitro and in vivo. Altogether, our results show that PLA2R1 is a novel substrate for ADAM10 and ADAM17, producing a soluble form that is increased in inflammatory conditions and likely exerts various functions in physiological and pathophysiological conditions including inflammation, cancer, and membranous nephropathy. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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