DC-SIGN

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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].

Contents

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].

Structure

image:DC-SIGN_4.jpg
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

The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for DC-SIGN.

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).

References

  1. ↑ 1.0 1.1 Geijtenbeek TB, Torensma R, van Vliet SJ, van Duijnhoven GC, Adema GJ, van Kooyk Y and Figdor CG. 2000. Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell. 100:575-585
  2. ↑ 2.0 2.1 2.2 Feinberg H, Mitchell DA, Drickamer K and Weis WI. 2001. Structural basis for selective recognition of oligosaccharides by DC-SIGN and DC-SIGNR. Science. 294:2163-2166
  3. ↑ Yu QD, Oldring AP, Powlesland AS, Tso CK, Yang C, Drickamer K and Taylor ME. 2009. Autonomous tetramerization domains in the glycan-binding receptors DC-SIGN and DC-SIGNR. J Mol Biol. 387:1075-1080
  4. ↑ Engering A, Geijtenbeek TB, van Vliet SJ, Wijers M, van Liempt E, Demaurex N, Lanzavecchia A, Fransen J, Figdor CG, Piguet V and van Kooyk Y. 2002. The dendritic cell-specific adhesion receptor DC-SIGN internalizes antigen for presentation to T cells. J Immunol. 168:2118-2126
  5. ↑ Caparros E, Munoz P, Sierra-Filardi E, Serrano-Gomez D, Puig-Kroger A, Rodriguez-Fernandez JL, Mellado M, Sancho J, Zubiaur M and Corbi AL. 2006. DC-SIGN ligation on dendritic cells results in ERK and PI3k activation and modulates cytokine production. Blood. 107:3950-3958
  6. ↑ Gringhuis SI, den Dunnen J, Litjens M, van Het Hof B, van Kooyk Y and Geijtenbeek TB. 2007. C-type lectin DC-SIGN modulates toll-like receptor signaling via raf-1 kinase-dependent acetylation of transcription factor NF-kb. Immunity. 26:605-616
  7. ↑ Gringhuis SI, den Dunnen J, Litjens M, van der Vlist M and Geijtenbeek TB. 2009. Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori. Nat Immunol. 10:1081-1088
  8. ↑ Powlesland AS, Ward EM, Sadhu SK, Guo Y, Taylor ME and Drickamer K. 2006. Widely divergent biochemical properties of the complete set of mouse DC-SIGN-related proteins. J Biol Chem. 281:20440-20449
  9. ↑ 9.0 9.1 9.2 Guo Y, Feinberg H, Conroy E, Mitchell DA, Alvarez R, Blixt O, Taylor ME, Weis WI and Drickamer K. 2004. Structural basis for distinct ligand-binding and targeting properties of the receptors DC-SIGN and DC-SIGNR. Nat Struct Mol Biol. 11:591-598
  10. ↑ Mitchell DA, Fadden AJ and Drickamer K. 2001. A novel mechanism of carbohydrate recognition by the C-type lectins DC-SIGN and DC-SIGNR. Subunit organization and binding to multivalent ligands. J Biol Chem. 276:28939-28945
  11. ↑ 11.0 11.1 van Liempt E, Bank CM, Mehta P, Garcia-Vallejo JJ, Kawar ZS, Geyer R, Alvarez RA, Cummings RD, Kooyk Y and van Die I. 2006. Specificity of DC-SIGN for mannose- and fucose-containing glycans. FEBS Lett. 580:6123-6131
  12. ↑ Bogoevska V, Horst A, Klampe B, Lucka L, Wagener C and Nollau P. 2006. CEACAM1, an adhesion molecule of human granulocytes, is fucosylated by fucosyltransferase IX and interacts with DC-SIGN of dendritic cells via Lewis X residues. Glycobiology. 16:197-209
  13. ↑ Bogoevska V, Nollau P, Lucka L, Grunow D, Klampe B, Uotila LM, Samsen A, Gahmberg CG and Wagener C. 2007. DC-SIGN binds ICAM-3 isolated from peripheral human leukocytes through Lewis X residues. Glycobiology. 17:324-333
  14. ↑ 14.0 14.1 Garcia-Vallejo JJ, van Liempt E, da Costa Martins P, Beckers C, van het Hof B, Gringhuis SI, Zwaginga JJ, van Dijk W, Geijtenbeek TB, van Kooyk Y and van Die I. 2008. DC-SIGN mediates adhesion and rolling of dendritic cells on primary human umbilical vein endothelial cells through Lewis Y antigen expressed on ICAM-2. Mol Immunol. 45:2359-2369
  15. ↑ Naarding MA, Ludwig IS, Groot F, Berkhout B, Geijtenbeek TB, Pollakis G and Paxton WA. 2005. Lewis x component in human milk binds DC-SIGN and inhibits HIV-1 transfer to CD4+ t lymphocytes. J Clin Invest. 115:3256-3264
  16. ↑ 16.0 16.1 Nonaka M, Ma BY, Murai R, Nakamura N, Baba M, Kawasaki N, Hodohara K, Asano S and Kawasaki T. 2008. Glycosylation-dependent interactions of C-type lectin DC-SIGN with colorectal tumor-associated Lewis glycans impair the function and differentiation of monocyte-derived dendritic cells. J Immunol. 180:3347-3356
  17. ↑ Maeda N, Nigou J, Herrmann JL, Jackson M, Amara A, Lagrange PH, Puzo G, Gicquel B and Neyrolles O. 2003. The cell surface receptor DC-SIGN discriminates between mycobacterium species through selective recognition of the mannose caps on lipoarabinomannan. J Biol Chem. 278:5513-5516
  18. ↑ Driessen NN, Ummels R, Maaskant JJ, Gurcha SS, Besra GS, Ainge GD, Larsen DS, Painter GF, Vandenbroucke-Grauls CM, Geurtsen J and Appelmelk BJ. 2009. Role of phosphatidylinositol mannosides in the interaction between mycobacteria and DC-SIGN. Infect Immun. 77:4538-4547
  19. ↑ van Die I, van Vliet SJ, Nyame AK, Cummings RD, Bank CM, Appelmelk B, Geijtenbeek TB and van Kooyk Y. 2003. The dendritic cell-specific C-type lectin DC-SIGN is a receptor for Schistosoma mansoni egg antigens and recognizes the glycan antigen Lewis x. Glycobiology. 13:471-478
  20. ↑ Meyer S, van Liempt E, Imberty A, van Kooyk Y, Geyer H, Geyer R and van Die I. 2005. DC-SIGN mediates binding of dendritic cells to authentic pseudo-Lewis Y glycolipids of Schistosoma mansoni cercariae, the first parasite-specific ligand of DC-SIGN. J Biol Chem. 280:37349-37359
  21. ↑ Feinberg H, Castelli R, Drickamer K, Seeberger PH and Weis WI. 2007. Multiple modes of binding enhance the affinity of DC-SIGN for high mannose N-linked glycans found on viral glycoproteins. J Biol Chem. 282:4202-4209
  22. ↑ Lozach PY, Lortat-Jacob H, de Lacroix de Lavalette A, Staropoli I, Foung S, Amara A, Houles C, Fieschi F, Schwartz O, Virelizier JL, Arenzana-Seisdedos F and Altmeyer R. 2003. DC-SIGN and L-SIGN are high affinity binding receptors for hepatitis c virus glycoprotein E2. J Biol Chem. 278:20358-20366
  23. ↑ Cambi A, Netea MG, Mora-Montes HM, Gow NA, Hato SV, Lowman DW, Kullberg BJ, Torensma R, Williams DL and Figdor CG. 2008. Dendritic cell interaction with Candida albicans critically depends on N-linked mannan. J Biol Chem. 283:20590-20599
  24. ↑ 24.0 24.1 Zhang P, Snyder S, Feng P, Azadi P, Zhang S, Bulgheresi S, Sanderson KE, He J, Klena J and Chen T. 2006. Role of N-acetylglucosamine within core lipopolysaccharide of several species of gram-negative bacteria in targeting DC-SIGN (CD209). J Immunol. 177:4002-4011
  25. ↑ 25.0 25.1 Steeghs L, van Vliet SJ, Uronen-Hansson H, van Mourik A, Engering A, Sanchez-Hernandez M, Klein N, Callard R, van Putten JP, van der Ley P, van Kooyk Y and van de Winkel JG. 2006. Neisseria meningitidis expressing Lgtb lipopolysaccharide targets DC-SIGN and modulates dendritic cell function. Cell Microbiol. 8:316-325
  26. ↑ 26.0 26.1 Bergman MP, Engering A, Smits HH, van Vliet SJ, van Bodegraven AA, Wirth HP, Kapsenberg ML, Vandenbroucke-Grauls CM, van Kooyk Y and Appelmelk BJ. 2004. Helicobacter pylori modulates the T helper cell 1/T helper cell 2 balance through phase-variable interaction between lipopolysaccharide and DC-SIGN. J Exp Med. 200:979-990
  27. ↑ Niemela R, Natunen J, Majuri ML, Maaheimo H, Helin J, Lowe JB, et al. Complementary acceptor and site specificities of Fuc-TIV and Fuc-TVII allow effective biosynthesis of sialyl-TriLex and related polylactosamines present on glycoprotein counterreceptors of selectins. J Biol Chem. 1998 Feb 13;273(7):4021-6
  28. ↑ Raetz CR and Whitfield C (2002) Lipopolysaccharide endotoxins. Annu. Rev. Biochem. 71, 635-700
  29. ↑ Tam, P-H and Lowary, TL (2009) Recent advances in mycobacterial cell wall glycan biosynthesis. Cur. Opin Struct. Biol. 13, 618-625
  30. ↑ Lussier, M, Sdicu, A-M and Bussey, H (1999) The KTR and MNN1 mannosyltransferase families of Saccharomyces cerevisiae. Biochim. Biophys. Acta 1426, 323-334
  31. ↑ DeBose-Boyd R, Nyame AK, Cummings RD. 1996. Schistosoma mansoni: characterization of an α1-3 fucosyltransferase in adult parasites. Exp Parasitol. 82: 1-10
  32. ↑ Marques Jr ET Jr, Ichikawa Y, Strand M, August JT, Hart GW, Schnaar RL. 2001. Fucosyltransferases in Schistosoma mansoni development. Glycobiology 11: 249-59
  33. ↑ DeBose-Boyd RA, Nyame AK, Jasmer DP, Cummings RD. 1998. The ruminant parasite Haemonchus contortus expresses an α1,3-fucosyltransferase capable of synthesizing the Lewis x and sialyl Lewis x antigens. Glycoconjugate J. 15: 789-98
  34. ↑ Hokke CH, Fitzpatrick JM and Hoffmann KF. 2007. Integrating transcriptome, proteome and glycome analyses of Schistosoma biology. Trends in Parasitology 23: 165-174
  35. ↑ Feinberg, H, Tso, CKW, Taylor, ME, Drickamer, K and Weis, WI. 2009. Segmented helical structure of the neck region of the glycan-binding receptor DC-SIGNR. J Mol Biol 394:613-620
  36. ↑ Feinberg, H, Guo, Y, Mitchell, DA, Drickamer, K and Weis, WI. 2005. Extended neck regions stabilze tetramers of the receptors DC-SIGN and DC-SIGNR. J Biol Chem 280:1327-1335
  37. ↑ van Gisbergen KP, Sanchez-Hernandez M, Geijtenbeek TB and van Kooyk Y. 2005. Neutrophils mediate immune modulation of dendritic cells through glycosylation-dependent interactions between MAC-1 and DC-SIGN. J Exp Med. 201:1281-1292
  38. ↑ Geijtenbeek TB, Krooshoop DJ, Bleijs DA, van Vliet SJ, van Duijnhoven GC, Grabovsky V, Alon R, Figdor CG and van Kooyk Y. 2000. DC-SIGN-ICAM-2 interaction mediates dendritic cell trafficking. Nat Immunol. 1:353-357
  39. ↑ Geijtenbeek TB, Kwon DS, Torensma R, van Vliet SJ, van Duijnhoven GC, Middel J, Cornelissen IL, Nottet HS, KewalRamani VN, Littman DR, Figdor CG and van Kooyk Y. 2000. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell. 100:587-597
  40. ↑ Navarro-Sanchez E, Altmeyer R, Amara A, Schwartz O, Fieschi F, Virelizier JL, Arenzana-Seisdedos F and Despres P. 2003. Dendritic-cell-specific ICAM3-grabbing non-integrin is essential for the productive infection of human dendritic cells by mosquito-cell-derived dengue viruses. EMBO Rep. 4:723-728
  41. ↑ Simmons G, Reeves JD, Grogan CC, Vandenberghe LH, Baribaud F, Whitbeck JC, Burke E, Buchmeier MJ, Soilleux EJ, Riley JL, Doms RW, Bates P and Pohlmann S. 2003. DC-SIGN and DC-SIGNR bind Ebola glycoproteins and enhance infection of macrophages and endothelial cells. Virology. 305:115-123
  42. ↑ Hodges A, Sharrocks K, Edelmann M, Baban D, Moris A, Schwartz O, Drakesmith H, Davies K, Kessler B, McMichael A and Simmons A. 2007. Activation of the lectin DC-SIGN induces an immature dendritic cell phenotype triggering Rho-GTPase activity required for HIV-1 replication. Nat Immunol. 8:569-577
  43. ↑ van Stijn CM, Meyer S, van den Broek M, Bruijns SC, van Kooyk Y, Geyer R and van Die I. 2010. Schistosoma mansoni worm glycolipids induce an inflammatory phenotype in human dendritic cells by cooperation of TLR4 and DC-SIGN. Mol Immunol. 47:1544-1552
  44. ↑ Geijtenbeek TB, Van Vliet SJ, Koppel EA, Sanchez-Hernandez M, Vandenbroucke-Grauls CM, Appelmelk B and Van Kooyk Y. 2003. Mycobacteria target DC-SIGN to suppress dendritic cell function. J Exp Med. 197:7-17
  45. ↑ Tanne A, Ma B, Boudou F, Tailleux L, Botella H, Badell E, Levillain F, Taylor ME, Drickamer K, Nigou J, Dobos KM, Puzo G, Vestweber D, Wild MK, Marcinko M, Sobieszczuk P, Stewart L, Lebus D, Gicquel B, Neyrolles O. 2009. A murine DC-SIGN homologue contributes to early host defense against Mycobacterium tuberculosis. J Exp Med 206: 2205-2220

Acknowledgements

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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