Carbohydrate (N-Acetylglucosamine 6-O) Sulfotransferase 4 (CHST4)

  • Steven D. Rosen
Reference work entry


The CHST4 gene encodes N-acetylglucosamine-6-O-sulfotransferase 2 (GlcNAc6ST-2). GlcNAc6ST-2 catalyzes the transfer of sulfate from the substrate 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to an N-acetylglucosamine residue at the nonreducing end of glycans. The enzyme belongs to a subfamily of carbohydrate sulfotransferases (originally referred to as the GST family) that modify the 6-hydroxyl of Gal, GalNAc, or GlcNAc (Fukuda et al. 2001; Hemmerich et al. 2001b; Grunwell and Bertozzi 2002). There are several GlcNAc6STs in this subfamily (five in human and four in mouse) (Uchimura and Rosen 2006). GlcNAc6ST-2 was originally identified and cloned based on its high expression in lymph node HEVs (high endothelial venules) as part of an effort to understand mechanisms of lymphocyte homing to lymph nodes. Together with GlcNAc6ST-1 (K. Uchimura, this volume), GlcNAc6ST-2 is responsible for the synthesis of 6-sulfo sLex, i.e., Siaα2-3Galβ1-4(Fucα1-3)(SO4 - 6)GlcNAc), a recognition determinant for the homing receptor L-selectin (see section “Biological Aspects” below).


High Endothelial Venule Lymphocyte Homing Recognition Determinant Lymphocyte Recruitment Ectopic Lymphoid Neogenesis 
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  1. Arata-Kawai H, Singer MS, Bistrup A, Zante A, Wang YQ, Ito Y, Bao X, Hemmerich S, Fukuda M, Rosen SD (2011) Functional contributions of N- and O-glycans to L-selectin ligands in murine and human lymphoid organs. Am J Pathol 178:423–433PubMedCrossRefGoogle Scholar
  2. Bistrup A, Bhakta S, Lee JK, Belov YY, Gunn MD, Zuo FR, Huang CC, Kannagi R, Rosen SD, Hemmerich S (1999) Sulfotransferases of two specificities function in the reconstitution of high endothelial cell ligands for L-selectin. J Cell Biol 145:899–910PubMedCrossRefGoogle Scholar
  3. Bistrup A, Tsay D, Shenoy P, Singer MS, Bangia N, Luther SA, Cyster JG, Ruddle NH, Rosen SD (2004) Detection of a sulfotransferase (HEC-GlcNAc6ST) in high endothelial venules of lymph nodes and in high endothelial venule-like vessels within ectopic lymphoid aggregates: relationship to the MECA-79 epitope. Am J Pathol 164:1635–1644PubMedCrossRefGoogle Scholar
  4. Bowman KG, Cook BN, de Graffenried CL, Bertozzi CR (2001) Biosynthesis of L-selectin ligands: sulfation of sialyl Lewis x-related oligosaccharides by a family of GlcNAc-6-sulfotransferases. Biochem 40:5382–5391CrossRefGoogle Scholar
  5. Bowman KG, Hemmerich S, Bhakta S, Singer MS, Bistrup A, Rosen SD, Bertozzi CR (1998) Identification of an N-acetylglucosamine-6-0-sulfotransferase activity specific to lymphoid tissue: an enzyme with a possible role in lymphocyte homing. Chem Biol 5:447–460PubMedCrossRefGoogle Scholar
  6. Browning JL, Allaire N, Ngam-Ek A, Notidis E, Hunt J, Perrin S, Fava RA (2005) Lymphotoxin-beta receptor signaling is required for the homeostatic control of HEV differentiation and function. Immunity 23:539–550PubMedCrossRefGoogle Scholar
  7. de Graffenried CL, Bertozzi CR (2003) Golgi localization of carbohydrate sulfotransferases is a determinant of L-selectin ligand biosynthesis. J Biol Chem 278:40282–40295PubMedCrossRefGoogle Scholar
  8. Degroote S, Lo-Guidice JM, Strecker G, Ducourouble MP, Roussel P, Lamblin G (1997) Characterization of an N-acetylglucosamine-6-O-sulfotransferase from human respiratory mucosa active on mucin carbohydrate chains. J Biol Chem 272:29493–29501PubMedCrossRefGoogle Scholar
  9. Dimitroff CJ, Lee JY, Fuhlbrigge RC, Sackstein R (2000) A distinct glycoform of CD44 is an L-selectin ligand on human hematopoietic cells. Proc Natl Acad Sci U S A 97:13841–13846PubMedCentralPubMedCrossRefGoogle Scholar
  10. Drayton DL, Liao S, Mounzer RH, Ruddle NH (2006) Lymphoid organ development: from ontogeny to neogenesis. Nat Immunol 7:344–353PubMedCrossRefGoogle Scholar
  11. Drayton DL, Ying X, Lee J, Lesslauer W, Ruddle NH (2003) Ectopic LT alpha beta directs lymphoid organ neogenesis with concomitant expression of peripheral node addressin and a HEV-restricted sulfotransferase. J Exp Med 197:1153–1163PubMedCentralPubMedCrossRefGoogle Scholar
  12. Fukuda M, Hiraoka N, Akama TO, Fukuda MN (2001) Carbohydrate-modifying sulfotransferases: structure, function, and pathophysiology. J Biol Chem 276:47747–47750PubMedGoogle Scholar
  13. Girard JP, Moussion C, Forster R (2012) HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nat Rev Immunol 12:762–773PubMedCrossRefGoogle Scholar
  14. Grunwell JR, Bertozzi CR (2002) Carbohydrate sulfotransferases of the GalNAc/Gal/GlcNAc6ST family. Biochem 41:13117–13126CrossRefGoogle Scholar
  15. Grunwell JR, Rath VL, Rasmussen J, Cabrilo Z, Bertozzi CR (2002) Characterization and mutagenesis of Gal/GlcNAc-6-O-sulfotransferases. Biochem 41:15590–15600CrossRefGoogle Scholar
  16. Hemmerich S, Bistrup A, Singer MS, van Zante A, Lee JK, Tsay D, Peters M, Carminati JL, Brennan TJ, Carver-Moore K, Leviten M, Fuentes ME, Ruddle NH, Rosen SD (2001a) Sulfation of L-selectin ligands by an HEV-restricted sulfotransferase regulates lymphocyte homing to lymph nodes. Immunity 15:237–247PubMedCrossRefGoogle Scholar
  17. Hemmerich S, Lee JK, Bhakta S, Bistrup A, Ruddle NR, Rosen SD (2001b) Chromosomal localization and genomic organization for the galactose/N-acetylgalactosamine/N-acetylglucosamine 6-O-sulfotransferase gene family. Glycobiol 11:75–87CrossRefGoogle Scholar
  18. Hemmerich S, Leffler H, Rosen SD (1995) Structure of the O-glycans in GlyCAM-1, an endothelial-derived ligand for L-selectin. J Biol Chem 270:12035–12047PubMedCrossRefGoogle Scholar
  19. Hirakawa J, Tsuboi K, Sato K, Kobayashi M, Watanabe S, Takakura A, Imai Y, Ito Y, Fukuda M, Kawashima H (2010) Novel anti-carbohydrate antibodies reveal the cooperative function of sulfated N- and O-glycans in lymphocyte homing. J Biol Chem 285:40864–40878PubMedCrossRefGoogle Scholar
  20. Hiraoka N, Kawashima H, Petryniak B, Nakayama J, Mitoma J, Marth JD, Lowe JB, Fukuda M (2004) Core 2 branching beta1,6-N-acetylglucosaminyltransferase and high endothelial venule-restricted sulfotransferase collaboratively control lymphocyte homing. J Biol Chem 279:3058–3067PubMedCrossRefGoogle Scholar
  21. Hiraoka N, Petryniak B, Nakayama J, Tsuboi S, Suzuki M, Yeh JC, Izawa D, Tanaka T, Miyasaka M, Lowe JB, Fukuda M (1999) A novel, high endothelial venule-specific sulfotransferase expresses 6-sulfo sialyl Lewis(x), an L-selectin ligand displayed by CD34. Immunity 11:79–89PubMedCrossRefGoogle Scholar
  22. Honke K, Taniguchi N (2002) Sulfotransferases and sulfated oligosaccharides. Med Res Rev 22:637–654PubMedCrossRefGoogle Scholar
  23. Imai Y, Lasky LA, Rosen SD (1993) Sulphation requirement for GlyCAM-1, an endothelial ligand for L-selectin. Nature 361:555–557PubMedCrossRefGoogle Scholar
  24. Kawashima H, Hirakawa J, Tobisawa Y, Fukuda M, Saga Y (2009) Conditional gene targeting in mouse high endothelial venules. J Immunol 182:5461–5468PubMedCentralPubMedCrossRefGoogle Scholar
  25. Kawashima H, Petryniak B, Hiraoka N, Mitoma J, Huckaby V, Nakayama J, Uchimura K, Kadomatsu K, Muramatsu T, Lowe JB, Fukuda M (2005) N-acetylglucosamine-6-O-sulfotransferases 1 and 2 cooperatively control lymphocyte homing through L-selectin ligand biosynthesis in high endothelial venules. Nat Immunol 6:1096–1104PubMedCrossRefGoogle Scholar
  26. Lee JK, Bistrup A, van Zante A, Rosen SD (2003) Activities and expression pattern of the carbohydrate sulfotransferase GlcNAc6ST-3 (I-GlcNAc6ST): functional implications. Glycobiol 13:245–254CrossRefGoogle Scholar
  27. Liao S, Bentley K, Lebrun M, Lesslauer W, Ruddle FH, Ruddle NH (2007) Transgenic LacZ under control of Hec-6st regulatory sequences recapitulates endogenous gene expression on high endothelial venules. Proc Natl Acad Sci U S A 104:4577–4582PubMedCentralPubMedCrossRefGoogle Scholar
  28. Martinet L, Garrido I, Filleron T, Le Guellec S, Bellard E, Fournie JJ, Rochaix P, Girard JP (2011) Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res 71:5678–5687PubMedCrossRefGoogle Scholar
  29. Mitoma J, Bao X, Petryanik B, Schaerli P, Gauguet JM, Yu SY, Kawashima H, Saito H, Ohtsubo K, Marth JD, Khoo KH, von Andrian UH, Lowe JB, Fukuda M (2007) Critical functions of N-glycans in L-selectin-mediated lymphocyte homing and recruitment. Nat Immunol 8:409–418PubMedCrossRefGoogle Scholar
  30. Mitsuoka C, Sawada-Kasugai M, Ando-Furui K, Izawa M, Nakanishi H, Nakamura S, Ishida H, Kiso M, Kannagi R (1998) Identification of a major carbohydrate capping group of the L-selectin ligand on high endothelial venules in human lymph nodes as 6-sulfo sialyl Lewis X. J Biol Chem 273:11225–11233PubMedCrossRefGoogle Scholar
  31. Ohmichi Y, Hirakawa J, Imai Y, Fukuda M, Kawashima H (2011) Essential role of peripheral node addressin in lymphocyte homing to nasal-associated lymphoid tissues and allergic immune responses. J Exp Med 208:1015–1025PubMedCentralPubMedCrossRefGoogle Scholar
  32. Ohmori K, Fukui F, Kiso M, Imai T, Yoshie O, Hasegawa H, Matsushima K, Kannagi R (2006) Identification of cutaneous lymphocyte-associated antigen as sialyl 6-sulfo Lewis X, a selectin ligand expressed on a subset of skin-homing helper memory T cells. Blood 107:3197–3204PubMedCrossRefGoogle Scholar
  33. Okayama H, Kumamoto K, Saitou K, Hayase S, Kofunato Y, Sato Y, Miyamoto K, Nakamura I, Ohki S, Koyama Y, Ishii Y, Takenoshita S (2011) Ectopic expression of MECA-79 as a novel prognostic indicator in gastric cancer. Can Sci 102:1088–1094CrossRefGoogle Scholar
  34. Pablos JL, Santiago B, Tsay D, Singer MS, Palao G, Galindo M, Rosen SD (2005) A HEV-restricted sulfotransferase is expressed in rheumatoid arthritis synovium and is induced by lymphotoxin-alpha/beta and TNF-alpha in cultured endothelial cells. BMC Immunol 6:6PubMedCentralPubMedCrossRefGoogle Scholar
  35. Paul P, Suwan J, Liu J, Dordick JS, Linhardt RJ (2012) Recent advances in sulfotransferase enzyme activity assays. Anal Bioanal Chem 403:1491–1500PubMedCentralPubMedCrossRefGoogle Scholar
  36. Rosen SD (2004) Ligands for L-selectin: homing, inflammation, and beyond. Annu Rev Immunol 22:129–156PubMedCrossRefGoogle Scholar
  37. Rosen SD, Tsay D, Singer MS, Hemmerich S, Abraham WM (2005) Therapeutic targeting of endothelial ligands for L-selectin (PNAd) in a sheep model of asthma. Am J Pathol 166:935–944PubMedCrossRefGoogle Scholar
  38. Seko A, Sumiya J, Yonezawa S, Nagata K, Yamashita K (2000) Biochemical differences between two types of N-acetylglucosamine: →6 sulfotransferases in human colonic adenocarcinomas and the adjacent normal mucosa: specific expression of a GlcNAc: →6 sulfotransferase in mucinous adenocarcinoma. Glycobiol 10:919–929CrossRefGoogle Scholar
  39. Seko A, Nagata K, Yonezawa S, Yamashita K (2002) Ectopic expression of a GlcNAc 6-O-sulfotransferase, GlcNAc6ST-2, in colonic mucinous adenocarcinoma. Glycobiol 12:379–388CrossRefGoogle Scholar
  40. Seko A, Kataoka F, Aoki D, Sakamoto M, Nakamura T, Hatae M, Yonezawa S, Yamashita K (2009) N-Acetylglucosamine 6-O-sulfotransferase-2 as a tumor marker for uterine cervical and corpus cancer. Glycoconj J26:1065–1073CrossRefGoogle Scholar
  41. Spiro RG, Yasumoto Y, Bhoyroo V (1996) Characterization of a rat liver Golgi sulphotransferase responsible for the 6-O-sulphation of N-acetylglucosamine residues in beta-linkage to mannose: role in assembly of sialyl-galactosyl-N-acetylglucosamine 6-sulphate sequence of N-linked oligosaccharides. Biochem J319:209–216Google Scholar
  42. Tangemann K, Bistrup A, Hemmerich S, Rosen SD (1999) Sulfation of a high endothelial venule-expressed ligand for L-selectin. Effects on tethering and rolling of lymphocytes. J Exp Med 190:935–942PubMedCentralPubMedCrossRefGoogle Scholar
  43. Tobisawa Y, Imai Y, Fukuda M, Kawashima H (2010) Sulfation of colonic mucins by N-acetylglucosamine 6-O-sulfotransferase-2 and its protective function in experimental colitis in mice. J Biol Chem 285:6750–6760PubMedCrossRefGoogle Scholar
  44. Uchimura K, El-Fasakhany FM, Hori M, Hemmerich S, Blink SE, Kansas GS, Kanamori A, Kumamoto K, Kannagi R, Muramatsu T (2002) Specificities of N-acetylglucosamine-6-O-sulfotransferases in relation to L-selectin ligand synthesis and tumor-associated enzyme expression. J Biol Chem 277:3979–3984PubMedCrossRefGoogle Scholar
  45. Uchimura K, Gauguet JM, Singer MS, Tsay D, Kannagi R, Muramatsu T, von Andrian UH, Rosen SD (2005) A major class of L-selectin ligands is eliminated in mice deficient in two sulfotransferases expressed in high endothelial venules. Nat Immunol 6:1105–1113PubMedCrossRefGoogle Scholar
  46. Uchimura K, Kadomatsu K, El-Fasakhany FM, Singer MS, Izawa M, Kannagi R, Takeda N, Rosen SD, Muramatsu T (2004) N-acetylglucosamine 6-O-sulfotransferase-1 regulates expression of L-selectin ligands and lymphocyte homing. J Biol Chem 279:35001–35008PubMedCrossRefGoogle Scholar
  47. Uchimura K, Rosen SD (2006) Sulfated L-selectin ligands as a therapeutic target in chronic inflammation. Trends Immunol 27:559–565PubMedCrossRefGoogle Scholar
  48. van Zante A, Gauguet JM, Bistrup A, Tsay D, von Andrian UH, Rosen SD (2003) Lymphocyte-HEV interactions in lymph nodes of a sulfotransferase-deficient mouse. J Exp Med 198:1289–1300PubMedCentralPubMedCrossRefGoogle Scholar
  49. Verdugo DE, Bertozzi CR (2002) A 96-well dot-blot assay for carbohydrate sulfotransferases. Anal Biochem 307:330–336PubMedCrossRefGoogle Scholar
  50. Yeh JC, Hiraoka N, Petryniak B, Nakayama J, Ellies LG, Rabuka D, Hindsgaul O, Marth JD, Lowe JB, Fukuda M (2001) Novel sulfated lymphocyte homing receptors and their control by a Core1 extension beta 1,3-N-acetylglucosaminyltransferase. Cell 105:957–969PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2014

Authors and Affiliations

  1. 1.Department of AnatomyUniversity of California, San FransiscoSan FranciscoUSA

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