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Dendritic cell-specific intracellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin (DC-SIGN, CD209) is a C-type lectin that plays roles in both cell-cell and host-pathogen interactions, and thus serves as a model for both processes. This glycan-binding protein (GBP) paradigm also serves as a model for other members of the C-type lectin family expressed on dendritic cells.
DC-SIGN is a type II membrane protein with a short aminoterminal cytoplasmic tail, a neck region and a single carboxyl terminal carbohydrate recognition domain (CRD)[1]. The primary structure of the CRD contains conserved residues consistent with classical mannose-specific CRDs [2]. Multivalent binding of glycan ligands by DC-SIGN is dependent on correct organization and presentation of the CRDs at the neck domains, which are crucial for tetramerization of DC-SIGN [3]. The cytoplasmic tail of DC-SIGN contains internalization motifs involved in the ligand-induced internalization of DC-SIGN [4], and can activate signaling pathways [5][6][7]. In mice several DC-SIGN-related proteins have been identified (SIGNR1-SIGNR8) [8].


CFG Participating Investigators contributing to the understanding of this paradigm

Many investigators, both CFG Participating Investigators (PIs) and non-PIs using CFG resources, have led extensive studies on DC-SIGN, particularly regarding structure-function relationships, interactions with pathogens, and signaling functions in dendritic cells.

  • PIs working on DC-SIGN include: Pedro Bonay, Angel Corbi, Kurt Drickamer, Juan Garcia-Vallejo, Donald Harn, Kayo Inaba, Benhur Lee, Olivier Neyrolles, Irma van Die, Yvette van Kooyk, William Weis, Martin Wild
  • Non-PIs who have used CFG resources to study DC-SIGN include: Brigitte Gicquel, Arne Skerra, Ralph Steinman

Progress toward understanding this GBP paradigm

This section documents what is currently known about DC-SIGN, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information about DC-SIGN can be found in its GBP Molecule Page in the CFG database.

Carbohydrate ligands

DC-SIGN recognizes both internal branched mannose residues as well as terminal di-mannoses, α1-3 and α1-4 fucosylated glycan structures and certain N-aceltylglucosamine containing molecules on self proteins and/or pathogens [2][9][10][11]

Endogenous ligands include

Glycan ligands from pathogens include

  • Mycobacterium tuberculosis lipoarabinomannan (ManLAM) and hexamannosylated phosphatidylinositol mannoside PIM6 [17][18]
  • Schistosoma mansoni glycans LeX, GalNAcβ1-4(Fucα1-3)GlcNAc-R (LDNF) and Fucα1-3Galβ1-4(Fucα1-3)GlcNAc-R (pseudo-LeY) [19][20]
  • Virus-associated high-mannose type glycans [21][22]
  • Candida albicans N-linked mannan [23]
  • Escherichia coli K12 N-acetylglucosamine (GlcNAc) residues within core LPS [24]
  • Neisseria meningitides GlcNAcβ1-3Galβ1-4Glc-R oligosaccharide of lgtB outer core LPS [25]
  • Helicobacter pylori LPS-associated LeX glycan antigens [26]

Cellular expression of GBP and ligands

DC-SIGN is expressed on dendritic cells and dendritic cell-like macrophages. Pathogens expressing DC-SIGN ligands include: Mycobacterium tuberculosis, Schistosoma mansoni, Candida albicans, Escherichia coli, Neisseria meningitides, Helicobacter pylori, and others (see above).

Biosynthesis of ligands

Endogenous glycans
The fucosyltransferase responsible in humans and mice for LeX biosynthesis is Fuc-TIV. T-cells also express Fuc-TVII, but this transferase is specific for sialyl-LeX [27].

Glycans on viruses
High mannose oligosaccharides on viral envelope proteins that are ligands for DC-SIGN result from incomplete processing of glycans in the pathway for biosynthesis of complex N-linked glycans (GT Database).

Glycans on bacteria
The biosynthesis pathways for the bacterial lipopolysaccharides have been extensively studied and the gene families responsible for the expression of different glycan sequences have been characterized.[28]

The mycobacterial transferases for synthesis of the lipo-arabinomannan (LAM) core and the extended ManLAM structures have been characterized.[29]

Glycans on fungi
Biosynthesis mannans on fungi has been well studied in a number of species. For example, in the yeast S. cerevisiae, the KRE2/MNT1 genes encode mannosyltransferases that synthesize both N- and O-linked mannans.[30]

Glycans on parasites
Some data give insight in the biosynthesis of DC-SIGN ligands in parasitic helminths. In Schistosoma mansoni [31][32] and Haemonchus contortus [33] α1,3-fucosyltransferases have been identified, which may be involved in generation of Galβ1-4(Fucα1-3)GlcNAc-R (Lewis X), and/or GalNAcβ1-4(Fucα1-3)GlcNAc-R (LDNF). Combined transcriptome (putative glycosyltransferase genes) and glycome analyses of Schistosoma revealed that female schistosomes synthesize preferably terminal LacNAc and Lewis X, whereas male worms synthesize more LDN/LDNF antigens [34].


Crystal structures of the CRD of DC-SIGN bound to a mannose-containing oligosaccharide and lacto-N-fucopentaose have been analyzed.[2][9] The first structure can be used to model the binding of the outer portion of a high mannose oligosaccharide and the second structure shows how the Lewisx trisaccharide fits into the binding site. The high mannose oligosaccharide makes extensive interactions in an extended binding site, while the more rigid Lewisx oligosaccharide binds primarily through the fucose residues, with some additional stabilizing interactions with the galactose. The overall structure of the tetrameric extracellular domain has been deduced from crystal structures of the repeats in the neck domain of the related protein DC-SIGNR (L-SIGN)[35] and oligomeric C-terminal fragments of DC-SIGN that contain the CRD[36].

Biological roles of GBP-ligand interaction

Biological roles for DC-SIGN include:

  • DC-SIGN mediates interactions between dendritic cells (DCs) and resting T cells [1] and between DCs and neutrophils [37].
  • DC-SIGN contributes to adhesion and rolling of DCs on primary human umbilical vein endothelial cells [38][14]
  • interactions of DC-SIGN with Lewis antigens on colorectal tumor cells impair the function and differentiation of dendritic cells [16]
  • DC-SIGN can mediate bacterial adherence and phagocytosis [24].
  • viruses target DC-SIGN to promote infection and spread to cells [39][40][41][42]
  • activation of DC-SIGN by pathogens can contribute to T helper type 1 (Th)1 cell activity [25][43]
  • some pathogens target DC-SIGN to suppress Th1 cell development [26][44]
  • the murine DC-SIGN homologue SIGNR3 contributes to early host defense against Mycobacterium tuberculosis [45]

CFG resources used in investigations


Glycan profiling

LeX antigens, which are potential ligands for DC-SIGN, have been identified by the Analytical Glycotechnology Core in the following cells of the immune system:

Human: B-cells, basophils, dendritic cells, eosinophils, human dermal lymphatic endothelial cells, macrophages, mast cells, monocytes, natural killer cells, neutrophils, peripheral blood mononuclear cells, T cells

Mouse: B1 cells, B2 cells, cytokine induced killer cells, eosinophils, macrophages

(all Analytical Glycotechnology Core data)

T-Cells, which would be the most relevant interacting partner, contain substantial levels of LeX in humans.

Glycogene microarray

Probes for human DC-SIGN have been included in all versions of the CFG glycogene chip.

Knockout mouse lines

Knockout mice for three potential DC-SIGN orthologues (DC-SIGN, SIGNR1, and SIGNR3) were created by the CFG and distributed to PIs, and their phenotypes were analyzed.

Glycan array

Glycan array analysis [9][11]and synthetic oligosaccharides were used to elucidate DC-SIGN glycan-binding specificity and analyze the mechanism of specific glycan binding. See all glycan array results for DC-SIGN here. See glycan array screening results for these related GBPs: langerin, DCIR, and DC-SIGNR.

Related GBPs

Other dendritic cell lectins include langerin (CFG data), DCIR (CFG data), and DCAR. Paralogs on other cells include DC-SIGNR (CFG data).


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The CFG is grateful to the following PIs for their contributions to this wiki page: Kurt Drickamer, Irma van Die, Yvette van Kooyk

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