HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) 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 Google Scholar Articles by Nigou, J. Articles by Puzo, G. PubMed PubMed Citation Articles by Nigou, J. Articles by Puzo, G. Pubmed/NCBI databases Substance via MeSH

Mannan Chain Length Controls Lipoglycans Signaling via and Binding to TLR2¹

Jérôme Nigou^2,*, Thierry Vasselon, Aurélie Ray^*, Patricia Constant^*, Martine Gilleron^*, Gurdyal S. Besra, Iain Sutcliffe^¶, Gérard Tiraby and Germain Puzo^*

^* Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5089, Department of Molecular Mechanisms of Mycobacterial Infections, Toulouse; Cayla Invivogen, Research Department, Toulouse; Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5535, Montpellier, France; and School of Biosciences, University of Birmingham, Birmingham, and ^¶ School of Applied Sciences, Northumbria University, Newcastle Upon Tyne, United Kingdom

TLR2 is a pattern-recognition receptor that is activated by a large variety of conserved microbial components, including lipoproteins, lipoteichoic acids, and peptidoglycan. Lipoglycans are TLR2 agonists found in some genera of the phylogenetic order Actinomycetales, including Mycobacterium. They are built from a mannosyl-phosphatidyl-myo-inositol anchor attached to a (16)-linked D-mannopyranosyl chain whose units can be substituted by D-mannopyranosyl and/or D-arabinofuranosyl units. At this time, little is known about the molecular bases underlying their ability to induce signaling via this receptor. We have recently shown that the anchor must be at least triacylated, including a diacylglyceryl moiety, whereas the contribution of the glycosidic moiety is not yet clearly defined. We show herein that lipoglycan activity is directly determined by mannan chain length. Indeed, activity increases with the number of units constituting the (16)-mannopyranosyl backbone but is also critically dependent on the substitution type of the 2-hydroxyl of these units. We thus provide evidence for the definition of a new pattern that includes the nonlipidic moiety of the molecules, most probably as a result of the (16)-mannopyranosyl backbone being a highly conserved structural feature among lipoglycans. Moreover, we demonstrate that lipoglycans can bind cell surface-expressed TLR2 and that their ability to induce signaling might be, at least in part, dictated by their avidity for the receptor. Finally, our data suggest that lipoglycans and lipoproteins have a common binding site. The present results are thus discussed in the light of the recently published crystal structure of a TLR1-TLR2-lipopeptide complex.

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 from Centre National de la Recherche Scientifique. G.S.B. was supported by a Personal Research Chair from James Bardrick, a Royal Society Wolfson Research Merit Award, as a former Lister Institute-Jenner Research Fellow, the Medical Research Council (G9901077 and G0500590), and The Wellcome Trust (081569/2/06/2).

² Address correspondence and reprint requests to Dr. Jérôme Nigou, Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5089, 205 route de Narbonne, 31077 Toulouse Cedex 4, France. E-mail address: jerome.nigou{at}ipbs.fr

³ Abbreviations used in this paper: GPI, glycosyl-phosphatidyl-myo-inositol; A-Pam₃CSK₄, Alexa Fluor 488-labeled synthetic lipopeptide; AraLAM, uncapped LAM; BCG, bacillus Calmette-Guérin; HEK-Flag-TLR2, HEK293 cells stably expressing a Flag-TLR2 protein; HSA, human serum albumin; LAM, lipoarabinomannan; LM, lipomannan; ManLAM, mannose-capped LAM; Manp, mannopyranose; MPI, mannosyl-phosphatidyl-myo-inositol; PILAM, phospho-myo-inositol-capped LAM; PIM, phosphatidyl-myo-inositol mannosides; ReqLAM, LAM from Rhodococcus equi; RruLAM, LAM from Rhodococcus ruber; RvLM, LM from Mycobacterium tuberculosis H37Rv; SaeLM, LM from Saccharothrix aerocolonigenes; TotLAM, LAM from Turicella otitidis; TpaLAM and TpaLM, LAM and LM, respectively, from Tsukamurella paurometabolum; Araf, arabinofuranose; CCD, charge-coupled device.