Mannan chain length controls lipoglycans signaling via and binding to TLR2.
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 (alpha1-->6)-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 (alpha1-->6)-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 (alpha1-->6)-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.
Nigou
Jérôme
J
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, France. jerome.nigou@ipbs.fr
Vasselon
Thierry
T
Ray
Aurélie
A
Constant
Patricia
P
Gilleron
Martine
M
Besra
Gurdyal S
GS
Sutcliffe
Iain
I
Tiraby
Gérard
G
Puzo
Germain
G
D001424:Bacterial Infections / Q000276:immunology; D002460:Cell Line; D006801:Humans; D008070:Lipopolysaccharides / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D008262:Macrophage Activation / Q000276:immunology; D008351:Mannans / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha
D008070:Lipopolysaccharides; D008351:Mannans; D016328:NF-kappa B; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha