title: Lipid structure influences the ability of glucose monocorynomycolate to signal through Mincle.
abstract: Mincle (macrophage-inducible C-type lectin) is a C-type lectin receptor that provides the capacity for immune sensing of a range of pathogen- and commensal-derived glycolipids. Mincle can recognize mycolic and/or corynomycolic acid esters of trehalose, glycerol and glucose from mycobacteria and corynebacteria. While simple straight-chain long fatty acids (e.g. behenic acid) can substitute for mycolic acid on trehalose and glycerol and maintain robust signalling through Mincle, glucose monobehenate has been reported to be much less active than glucose monocorynomycolate (GMCM). We report the preparation of a range of analogues of GMCM to explore structural requirements in the lipid chain for signalling through Mincle. GMCM analogues bearing simple straight chain or branched fatty acid esters provided only weak signalling through human and mouse Mincle. A GMCM variant with a truncated (pentyl) α-chain provided attenuated signalling, whereas an analogue with an extended (tricosyl; C23) α-chain signalled as potently as GMCM. This work suggests that Mincle has the ability to survey mycolate-derived glycolipids from actinomycetes, distinguishing non-pathogenic (e.g. Rhodococcus spp.) and pathogenic (e.g. Mycobacterium tuberculosis) species on the basis of α-chain length. Finally, an α-phenyldodecyl analogue of GMCM possessed similar potency to GMCM and was only slightly less potent than trehalose dimycolate (cord factor), showing that large functional groups may be tolerated in the α-chain.
authors.affiliation: School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010 Australia. sjwill@unimelb.edu.au.
authors.forename: Phillip L
authors.initials: PL
authors.lastname: van der Peet
authors.affiliation: Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nagata
authors.affiliation: School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010 Australia. sjwill@unimelb.edu.au.
authors.forename: Sayali
authors.initials: S
authors.lastname: Shah
authors.affiliation: School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010 Australia. sjwill@unimelb.edu.au.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: White
authors.affiliation: Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Yamasaki
authors.affiliation: School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010 Australia. sjwill@unimelb.edu.au.
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Williams
mesh_terms: D018360:Crystallography, X-Ray; D006017:Glycolipids / Q000737:chemistry / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D012240:Rhodococcus / Q000472:pathogenicity; D015398:Signal Transduction
chemical_list: C482593:CLEC4D protein, human; C113583:Clecsf8 protein, mouse; D006017:Glycolipids; D037181:Lectins, C-Type; D008055:Lipids; D008565:Membrane Proteins; D011971:Receptors, Immunologic; C048938:glucose mycolate