RRC ID 69793
Author Marutani T, Nishino K, Miyaji T, Kamada K, Ohura K, Kiso Y, Mukai H.
Title Mitocryptide-2: Identification of Its Minimum Structure for Specific Activation of FPR2-Possible Receptor Switching from FPR2 to FPR1 by Its Physiological C-terminal Cleavages.
Journal Int J Mol Sci
Abstract Mitocryptides are a novel family of endogenous neutrophil-activating peptides originating from various mitochondrial proteins. Mitocryptide-2 (MCT-2) is one of such neutrophil-activating peptides, and is produced as an N-formylated pentadecapeptide from mitochondrial cytochrome b. Although MCT-2 is a specific endogenous ligand for formyl peptide receptor 2 (FPR2), the chemical structure within MCT-2 that is responsible for FPR2 activation is still obscure. Here, we demonstrate that the N-terminal heptapeptide structure of MCT-2 with an N-formyl group is the minimum structure that specifically activates FPR2. Moreover, the receptor molecule for MCT-2 is suggested to be shifted from FPR2 to its homolog formyl peptide receptor 1 (FPR1) by the physiological cleavages of its C-terminus. Indeed, N-terminal derivatives of MCT-2 with seven amino acid residues or longer caused an increase of intracellular free Ca2+ concentration in HEK-293 cells expressing FPR2, but not in those expressing FPR1. Those MCT-2 derivatives also induced β-hexosaminidase secretion in neutrophilic/granulocytic differentiated HL-60 cells via FPR2 activation. In contrast, MCT-2(1-4), an N-terminal tetrapeptide of MCT-2, specifically activated FPR1 to promote those functions. Moreover, MCT-2 was degraded in serum to produce MCT-2(1-4) over time. These findings suggest that MCT-2 is a novel critical factor that not only initiates innate immunity via the specific activation of FPR2, but also promotes delayed responses by the activation of FPR1, which may include resolution and tissue regeneration. The present results also strongly support the necessity of considering the exact chemical structures of activating factors for the investigation of innate immune responses.
Volume 22(8)
Published 2021-4-15
DOI 10.3390/ijms22084084
PII ijms22084084
PMID 33920954
PMC PMC8071274
MeSH Amino Acid Sequence Amino Acid Substitution Calcium / metabolism Cell Differentiation Circular Dichroism HEK293 Cells HL-60 Cells Humans Immunity, Innate Models, Biological Molecular Docking Simulation Neutrophils / metabolism Peptides / blood Peptides / chemistry* Peptides / metabolism* Receptors, Formyl Peptide / chemistry* Receptors, Formyl Peptide / metabolism* Receptors, Lipoxin / chemistry* Receptors, Lipoxin / metabolism* Time Factors beta-N-Acetylhexosaminidases / metabolism
IF 4.556
Human and Animal Cells HL60(RCB0041)