DC-SIGN mediates binding of dendritic cells to authentic pseudo-LewisY glycolipids of Schistosoma mansoni cercariae, the first parasite-specific ligand of DC-SIGN

Sandra Meyer, Ellis van Liempt, Anne Imberty, Yvette van Kooyk, Hildegard Geyer, Rudolf Geyer, Irma van Die

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

During schistosomiasis, parasite-derived glycoconjugates play a key role in manipulation of the host immune response, associated with persistence of the parasite. Among the candidate host receptors that are triggered by glycoconjugates are C-type lectins (CLRs) on dendritic cells (DCs), which in concerted action with Toll-like receptors determine the balance in DCs between induction of immunity versus tolerance. Here we report that the CLR DC-SIGN mediates adhesion of DCs to authentic glycolipids derived from Schistosoma mansoni cercariae and their excretory/secretory products. Structural characterization of the glycolipids, in combination with solid phase and cellular binding studies revealed that DC-SIGN binds to the carbohydrate moieties of both glycosphingolipid species with Galbeta1-4(Fucalpha1-3)GlcNAc (Lewis(X)) and Fucalpha1-3Galbeta1-4(Fucalpha1-3)GlcNAc (pseudo-Lewis(Y)) determinants. Importantly, these data indicate that surveying DCs in the skin may encounter schistosome-derived glycolipids immediately after infection. Recent analysis of crystals of the carbohydrate binding domain of DC-SIGN bound to Lewis(X) provided insight into the ability of DC-SIGN to bind fucosylated ligands. Using molecular modeling we showed that the observed binding of the schistosome-specific pseudo-Lewis(Y) to DC-SIGN is not directly compatible with the model described. To fit pseudo-Lewis(Y) into the model, the orientation of the side chain of Phe(313) in the secondary binding site of DC-SIGN was slightly changed, which results in a perfect stacking of Phe(313) with the hydrophobic side of the galactose-linked fucose of pseudo-Lewis(Y). We propose that pathogens such as S. mansoni may use the observed flexibility in the secondary binding site of DC-SIGN to target DCs, which may contribute to immune escape.

Original languageEnglish
Pages (from-to)37349-37359
Number of pages11
JournalJournal of Biological Chemistry
Volume280
Issue number45
DOIs
Publication statusPublished - 11 Nov 2005

Cite this

@article{54840d12d286429b8cc1738cd2611601,
title = "DC-SIGN mediates binding of dendritic cells to authentic pseudo-LewisY glycolipids of Schistosoma mansoni cercariae, the first parasite-specific ligand of DC-SIGN",
abstract = "During schistosomiasis, parasite-derived glycoconjugates play a key role in manipulation of the host immune response, associated with persistence of the parasite. Among the candidate host receptors that are triggered by glycoconjugates are C-type lectins (CLRs) on dendritic cells (DCs), which in concerted action with Toll-like receptors determine the balance in DCs between induction of immunity versus tolerance. Here we report that the CLR DC-SIGN mediates adhesion of DCs to authentic glycolipids derived from Schistosoma mansoni cercariae and their excretory/secretory products. Structural characterization of the glycolipids, in combination with solid phase and cellular binding studies revealed that DC-SIGN binds to the carbohydrate moieties of both glycosphingolipid species with Galbeta1-4(Fucalpha1-3)GlcNAc (Lewis(X)) and Fucalpha1-3Galbeta1-4(Fucalpha1-3)GlcNAc (pseudo-Lewis(Y)) determinants. Importantly, these data indicate that surveying DCs in the skin may encounter schistosome-derived glycolipids immediately after infection. Recent analysis of crystals of the carbohydrate binding domain of DC-SIGN bound to Lewis(X) provided insight into the ability of DC-SIGN to bind fucosylated ligands. Using molecular modeling we showed that the observed binding of the schistosome-specific pseudo-Lewis(Y) to DC-SIGN is not directly compatible with the model described. To fit pseudo-Lewis(Y) into the model, the orientation of the side chain of Phe(313) in the secondary binding site of DC-SIGN was slightly changed, which results in a perfect stacking of Phe(313) with the hydrophobic side of the galactose-linked fucose of pseudo-Lewis(Y). We propose that pathogens such as S. mansoni may use the observed flexibility in the secondary binding site of DC-SIGN to target DCs, which may contribute to immune escape.",
keywords = "Animals, Binding Sites, Carbohydrate Sequence, Cell Adhesion, Cell Adhesion Molecules/chemistry, Cells, Cultured, Dendritic Cells/immunology, Glycolipids/chemistry, Humans, Lectins, C-Type/chemistry, Lewis Blood-Group System/chemistry, Protein Binding, Receptors, Cell Surface/chemistry, Schistosoma mansoni/immunology, Species Specificity, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Substrate Specificity",
author = "Sandra Meyer and {van Liempt}, Ellis and Anne Imberty and {van Kooyk}, Yvette and Hildegard Geyer and Rudolf Geyer and {van Die}, Irma",
year = "2005",
month = "11",
day = "11",
doi = "10.1074/jbc.M507100200",
language = "English",
volume = "280",
pages = "37349--37359",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "45",

}

DC-SIGN mediates binding of dendritic cells to authentic pseudo-LewisY glycolipids of Schistosoma mansoni cercariae, the first parasite-specific ligand of DC-SIGN. / Meyer, Sandra; van Liempt, Ellis; Imberty, Anne; van Kooyk, Yvette; Geyer, Hildegard; Geyer, Rudolf; van Die, Irma.

In: Journal of Biological Chemistry, Vol. 280, No. 45, 11.11.2005, p. 37349-37359.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - DC-SIGN mediates binding of dendritic cells to authentic pseudo-LewisY glycolipids of Schistosoma mansoni cercariae, the first parasite-specific ligand of DC-SIGN

AU - Meyer, Sandra

AU - van Liempt, Ellis

AU - Imberty, Anne

AU - van Kooyk, Yvette

AU - Geyer, Hildegard

AU - Geyer, Rudolf

AU - van Die, Irma

PY - 2005/11/11

Y1 - 2005/11/11

N2 - During schistosomiasis, parasite-derived glycoconjugates play a key role in manipulation of the host immune response, associated with persistence of the parasite. Among the candidate host receptors that are triggered by glycoconjugates are C-type lectins (CLRs) on dendritic cells (DCs), which in concerted action with Toll-like receptors determine the balance in DCs between induction of immunity versus tolerance. Here we report that the CLR DC-SIGN mediates adhesion of DCs to authentic glycolipids derived from Schistosoma mansoni cercariae and their excretory/secretory products. Structural characterization of the glycolipids, in combination with solid phase and cellular binding studies revealed that DC-SIGN binds to the carbohydrate moieties of both glycosphingolipid species with Galbeta1-4(Fucalpha1-3)GlcNAc (Lewis(X)) and Fucalpha1-3Galbeta1-4(Fucalpha1-3)GlcNAc (pseudo-Lewis(Y)) determinants. Importantly, these data indicate that surveying DCs in the skin may encounter schistosome-derived glycolipids immediately after infection. Recent analysis of crystals of the carbohydrate binding domain of DC-SIGN bound to Lewis(X) provided insight into the ability of DC-SIGN to bind fucosylated ligands. Using molecular modeling we showed that the observed binding of the schistosome-specific pseudo-Lewis(Y) to DC-SIGN is not directly compatible with the model described. To fit pseudo-Lewis(Y) into the model, the orientation of the side chain of Phe(313) in the secondary binding site of DC-SIGN was slightly changed, which results in a perfect stacking of Phe(313) with the hydrophobic side of the galactose-linked fucose of pseudo-Lewis(Y). We propose that pathogens such as S. mansoni may use the observed flexibility in the secondary binding site of DC-SIGN to target DCs, which may contribute to immune escape.

AB - During schistosomiasis, parasite-derived glycoconjugates play a key role in manipulation of the host immune response, associated with persistence of the parasite. Among the candidate host receptors that are triggered by glycoconjugates are C-type lectins (CLRs) on dendritic cells (DCs), which in concerted action with Toll-like receptors determine the balance in DCs between induction of immunity versus tolerance. Here we report that the CLR DC-SIGN mediates adhesion of DCs to authentic glycolipids derived from Schistosoma mansoni cercariae and their excretory/secretory products. Structural characterization of the glycolipids, in combination with solid phase and cellular binding studies revealed that DC-SIGN binds to the carbohydrate moieties of both glycosphingolipid species with Galbeta1-4(Fucalpha1-3)GlcNAc (Lewis(X)) and Fucalpha1-3Galbeta1-4(Fucalpha1-3)GlcNAc (pseudo-Lewis(Y)) determinants. Importantly, these data indicate that surveying DCs in the skin may encounter schistosome-derived glycolipids immediately after infection. Recent analysis of crystals of the carbohydrate binding domain of DC-SIGN bound to Lewis(X) provided insight into the ability of DC-SIGN to bind fucosylated ligands. Using molecular modeling we showed that the observed binding of the schistosome-specific pseudo-Lewis(Y) to DC-SIGN is not directly compatible with the model described. To fit pseudo-Lewis(Y) into the model, the orientation of the side chain of Phe(313) in the secondary binding site of DC-SIGN was slightly changed, which results in a perfect stacking of Phe(313) with the hydrophobic side of the galactose-linked fucose of pseudo-Lewis(Y). We propose that pathogens such as S. mansoni may use the observed flexibility in the secondary binding site of DC-SIGN to target DCs, which may contribute to immune escape.

KW - Animals

KW - Binding Sites

KW - Carbohydrate Sequence

KW - Cell Adhesion

KW - Cell Adhesion Molecules/chemistry

KW - Cells, Cultured

KW - Dendritic Cells/immunology

KW - Glycolipids/chemistry

KW - Humans

KW - Lectins, C-Type/chemistry

KW - Lewis Blood-Group System/chemistry

KW - Protein Binding

KW - Receptors, Cell Surface/chemistry

KW - Schistosoma mansoni/immunology

KW - Species Specificity

KW - Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

KW - Substrate Specificity

U2 - 10.1074/jbc.M507100200

DO - 10.1074/jbc.M507100200

M3 - Article

VL - 280

SP - 37349

EP - 37359

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 45

ER -