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 motives 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

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 [9][10][11][12]

Endogenous ligands include

Glycan ligands from pathogens include

  • Mycobacterium tuberculosis lipoarabinomannan (ManLAM) and hexamannosylated phosphatidylinositol mannoside PIM6 [18][19]
  • Schistosoma mansoni glycans LeX, GalNAcβ1-4(Fucα1-3)GlcNAc-R (LDNF) and Fucα1-3Galβ1-4(Fucα1-3)GlcNAc-R (pseudo-LeY) [20][21]
  • Virus-associated high-mannose type glycans [22][23]
  • Candida albicans N-linked mannan [24]
  • Escherichia coli K12 N-acetylglucosamine (GlcNAc) residues within core LPS [25]
  • Neisseria meningitides GlcNAcβ1-3Galβ1-4Glc-R oligosaccharide of lgtB outer core LPS [26]
  • Helicobacter pylori LPS-associated LeX glycan antigens [27]


Cellular expression

DC-SIGN is expressed on dendritic cells and dendritic cell-like macrophages

Structure


Biological roles of GBP-ligand interaction

Biological roles for DC-SIGN include:

  • mediating interactions between dendritic cells (DCs) and resting T cells [1] and between DCs and neutrophils [28].
  • contributing to adhesion and rolling of DCs on primary human umbilical vein endothelial cells [29][15]
  • interactions of DC-SIGN with Lewis antigens on colorectal tumor cells impair the function and differentiation of dendritic cells [30]
  • mediates bacterial adherence and phagocytosis [25].
  • viruses target DC-SIGN to promote infection and spread to cells [31][32][33][34][35]
  • activation of DC-SIGN by pathogens can contribute to T helper type 1 (Th)1 cell activity [26][36]
  • some pathogens target DC-SIGN to suppress Th1 cell development [27][37]
  • the murine DC-SIGN homologue SIGNR3 contributes to early host defense against Mycobacterium tuberculosis [38]


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


Glycogene microarray


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 and synthetic oligosaccharides were used to elucidate DC-SIGN glycan-binding specificity and analyze the mechanism of specific glycan binding.


Related GBPs

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

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. 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. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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
  15. 15.0 15.1 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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
  22. 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
  23. 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
  24. 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
  25. 25.0 25.1 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
  26. 26.0 26.1 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
  27. 27.0 27.1 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
  28. 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
  29. 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
  30. 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
  31. 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
  32. 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
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  34. 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
  35. 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
  36. 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
  37. 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
  38. 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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