Human mitochondria-derived N-formylated peptides are novel agonists equally active on FPR and FPRL1, while Listeria monocytogenes-derived peptides preferentially activate FPR |
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Authors: | Rabiet Marie-Josèphe Huet Emilie Boulay François |
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Affiliation: | CEA Grenoble, Département de Dynamique et Réponse Cellulaires, Laboratoire de Biochimie et de Biophysique des Systèmes Intégrés, UMR 5092 CEA/CNRS/Université Joseph Fourier, Grenoble, France. mjrabiet@cea.fr |
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Abstract: | N-formyl peptides are cleavage products of bacterial and mitochondrial proteins, and can attract leukocytes to sites of infection or tissue damage. In this study, HL-60 cell lines expressing the human N-formyl peptide receptor FPR or its two homologues (FPRL1, FPRL2) were used to determine the receptor selectivity of N-formylated peptides derived from Listeria monocytogenes or from human mitochondrial proteins. Bacterial peptides were 100-fold more potent on FPR than on FPRL1, whereas none of them could trigger intracellular signaling through FPRL2. In contrast, N-formylated hexapeptides corresponding to the N terminus of mitochondrial NADH dehydrogenase subunits 4 (fMLKLIV) and 6 (fMMYALF), and cytochrome c oxidase subunit I (fMFADRW) were equally potent on FPR and FPRL1. They triggered cellular responses with the following order of potency: fMMYALF > fMLKLIV > fMFADRW, with an EC50, in a Fura-2 calcium mobilization assay, of 10 nM, 44 nM, and 160 nM on FPR-expressing cells, and 15 nM, 55 nM and 120 nM on FPRL1-expressing cells. fMMYALF was also a low-affinity agonist of FPRL2 (EC50 of 1 microM) and was chemotactic for both FPRL1- and FPRL2-expressing cells. We identified novel mitochondrial host-derived agonists for human N-formyl-peptide receptors that might play a role in inflammatory or degenerative processes linked to their stimulation. |
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Keywords: | Human Neutrophils Chemotaxis Inflammation Signal transduction |
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