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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0801523v1 183/10/6569    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Prat, C. Articles by van Kessel, K. P. M. PubMed PubMed Citation Articles by Prat, C. Articles by van Kessel, K. P. M.

A Homolog of Formyl Peptide Receptor-Like 1 (FPRL1) Inhibitor from Staphylococcus aureus (FPRL1 Inhibitory Protein) That Inhibits FPRL1 and FPR¹

Cristina Prat,^* Pieter-Jan Haas,^* Jovanka Bestebroer,^* Carla J. C. de Haas,^* Jos A. G. van Strijp,^* and Kok P. M. van Kessel^2*

^*Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands; and Microbiology Department, Hospital Universitari Germans Trias i Pujol, Universitat Autonoma de Barcelona, Barcelona, Spain

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 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III (expediente 01/F062) and Sociedad Española de Enfermedades Infecciosas y Microbiologia Clinica (both to C. P.).

² Address correspondence and reprint requests to Dr. Kok P. M. van Kessel, Medical Microbiology, University Medical Center Utrecht, room G04.614, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. E-mail address: k.kessel{at}umcutrecht.nl

³ Abbreviations used in this paper: GPCR, G protein-coupled receptor; Aβ, amyloid β; CHIPS, chemotaxis inhibitory protein of S. aureus; FLIPr, FPRL1 inhibitory protein; FPR, formyl peptide receptor; FPRL, FPR-like receptor; HSA, human serum albumin; LTB₄, leukotriene B₄; PAF, platelet-activating factor; PrP, prion protein.