A homolog of formyl peptide receptor-like 1 (FPRL1) inhibitor from Staphylococcus aureus (FPRL1 inhibitory protein) that inhibits FPRL1 and FPR.
The members of the formyl peptide receptor (FPR) family are involved in the sensing of chemoattractant substances, including bacteria-derived N-formylated peptides and host-derived peptides and proteins. We have recently described two chemoattractant receptor inhibitors from Staphylococcus aureus. Chemotaxis inhibitory protein of S. aureus (CHIPS) blocks the formyl peptide receptor (FPR) and the receptor for complement C5a (C5aR), while FPR-like 1 (FPRL1) inhibitory protein (FLIPr) blocks the FPRL1. Here, we describe another staphylococcal chemoattractant-inhibiting protein with 73% overall homology to FLIPr and identical first 25 aa, which we termed FLIPr-like. This protein inhibits neutrophil calcium mobilization and chemotaxis induced by the FPRL1-ligand MMK-1 and FPR-ligand fMLP. While its FPRL1-inhibitory activity lies in the comparable nanomolar range of FLIPr, its antagonism of the FPR is approximately 100-fold more potent than that of FLIPr and comparable to that of CHIPS. The second N-terminal phenylalanine was required for its inhibition of the FPR, but it was dispensable for the FPRL1. Furthermore, the deletion of the first seven amino acids reduced its antagonism of the FPRL1, and the exchange of the first six amino acids with that of CHIPS-conferred receptor specificity. Finally, studies with cells transfected with several chemoattractant receptors confirmed that FLIPr-like specifically binds to the FPR and FPRL1. In conclusion, the newly described excreted protein from S. aureus, FLIPr-like, is a potent inhibitor of the FPR- and FPRL1-mediated neutrophil responses and may be used to selectively modulate these chemoattractant receptors.
Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands.
Cristina
C
Prat
Pieter-Jan
PJ
Haas
Jovanka
J
Bestebroer
Carla J C
CJ
de Haas
Jos A G
JA
van Strijp
Kok P M
KP
van Kessel
D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a / Q000276:immunology / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000037:antagonists & inhibitors*; D013211:Staphylococcus aureus / Q000276:immunology
D001426:Bacterial Proteins; C105101:FPR2 protein, human; C516018:FPRL1 inhibitory protein, S aureus; C408903:MMK-1 peptide; D010455:Peptides; D044087:Receptor, Anaphylatoxin C5a; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C493134:chemotaxis inhibitory protein, Staphylococcus aureus