Human mitochondria-derived N-formylated peptides are novel agonists equally active on FPR and FPRL1, while Listeria monocytogenes-derived peptides preferentially activate FPR.
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.
Rabiet
Marie-Josèphe
MJ
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
Huet
Emilie
E
Boulay
François
F
D002118:Calcium / Q000378:metabolism; D002633:Chemotaxis / Q000502:physiology; D018922:HL-60 Cells; D006801:Humans; D008089:Listeria monocytogenes / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism*; D009245:NADH Dehydrogenase / Q000502:physiology; D010446:Peptide Fragments / Q000502:physiology; D044042:Receptors, Formyl Peptide / Q000819:agonists* / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000819:agonists* / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
C105101:FPR2 protein, human; C469985:FPR3 protein, human; D010446:Peptide Fragments; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009245:NADH Dehydrogenase; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium