Skip to main content

Advertisement

Log in

Molecular physiology and pathology of the nucleotide sugar transporter family (SLC35)

  • The ABC of Solute carriers
  • Guest Editor: Matthias A. Hediger
  • Published:
Pflügers Archiv Aims and scope Submit manuscript

Abstract

The solute carrier family SLC35 consists of at least 17 molecular species in humans. The family members so far characterized encode nucleotide sugar transporters localizing at the Golgi apparatus and/or the endoplasmic reticulum (ER). These transporters transport nucleotide sugars pooled in the cytosol into the lumen of these organelles, where most glycoconjugate synthesis occurs. Pathological analyses and developmental studies of small, multicellular organisms deficient in nucleotide sugar transporters have shown these transporters to be involved in tumour metastasis, cellular immunity, organogenesis and morphogenesis. Leukocyte adhesion deficiency type II (LAD II) or the congenital disorder of glycosylation type IIc (CDG IIc) are the sole human congenital disorders known to date that are caused by a defect of GDP-fucose transport. Along with LAD II, the possible involvement of nucleotide sugar transporters in disorders of connective tissues and muscles is also discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1.
Fig. 2.
Fig. 3A–D.

Similar content being viewed by others

References

  1. Eckhardt M, Gotza B, Gerardy-Schahn R (1999) Membrane topology of the mammalian CMP-sialic acid transporter. J Biol Chem 274:8779–8787

    Article  CAS  PubMed  Google Scholar 

  2. Hirschberg CB, Snider MD (1987) Topography of glycosylation in the rough endoplasmic reticulum and Golgi apparatus. Annu Rev Biochem 56:63–87

    Article  CAS  PubMed  Google Scholar 

  3. Kawakita M, Ishida N, Miura N, Sun-Wada G-H, Yoshioka S (1998) Nucleotide sugar transporters: elucidation of their molecular identity and its implication for future studies. J Biochem (Tokyo) 123:777–785

    Google Scholar 

  4. Hirschberg CB, Robbins PW, Abeijon C (1998) Transporters of nucleotide sugars, ATP, and nucleotide sulfate in the endoplasmic reticulum and Golgi apparatus. Annu Rev Biochem 67:49–69

    Article  CAS  PubMed  Google Scholar 

  5. Gerardy-Schahn R, Oelmann S, Bakker H (2001) Nucleotide sugar transporters: biological and functional aspects. Biochimie 83:775–782

    Article  CAS  PubMed  Google Scholar 

  6. Kean EL (1970) Nuclear cytidine 5′-monophosphosialic acid synthetase. J Biol Chem 245:2301–2308

    CAS  PubMed  Google Scholar 

  7. Münster AK, Eckhardt M, Potvin B, Mülenhoff M, Stanley P, Gerardy-Schahn R (1998) Mammalian cytidine 5′-monophosphate N-acetylneuraminic acid synthetase: a nuclear protein with evolutionarily conserved structural motifs. Proc Natl Acad Sci USA 95:9140–9145

    Article  CAS  PubMed  Google Scholar 

  8. Kuhn NJ, White A (1975) The topography of lactose synthesis. Biochem J 148:77–84

    CAS  PubMed  Google Scholar 

  9. Kuhn NJ, White A (1976) Evidence for specific transport of uridine diphosphate galactose across the Golgi membrane of rat mammary gland. Biochem J 154:243–244

    CAS  PubMed  Google Scholar 

  10. Kuhn NJ, White A (1977) The role of nucleoside diphosphatase in a uridine nucleotide cycle associated with lactose synthesis in rat mammary-gland Golgi apparatus. Biochem J 168:423–433

    CAS  PubMed  Google Scholar 

  11. Kornfeld R, Kornfeld S (1985) Assembly of asparagine-linked oligosaccharides. Annu Rev Biochem 54:631–664

    Article  CAS  PubMed  Google Scholar 

  12. Stanley P, Siminovitch L (1977) Complementation between mutants of CHO cells resistant to a variety of plant lectins. Somatic Cell Genet 3:391–405

    CAS  PubMed  Google Scholar 

  13. Deutscher SL, Hirschberg CB (1986) Mechanism of galactosylation in the Golgi apparatus. A Chinese hamster ovary cell mutant deficient in translocation of UDP-galactose across Golgi vesicle membranes. J Biol Chem 261:96–100

    CAS  PubMed  Google Scholar 

  14. Deutscher SL, Nuwayhid N, Stanley P, Briles EI, Hirschberg CB (1984) Translocation across Golgi vesicle membranes: a CHO glycosylation mutant deficient in CMP-sialic acid transport. Cell 39:295–299

    Google Scholar 

  15. Abeijon C, Robbins PW, Hirschberg CB (1996) Molecular cloning of the Golgi apparatus uridine diphosphate-N-acetylglucosamine transporter from Kluyveromyces lactis. Proc Natl Acad Sci USA 93:5963–5968

    Article  CAS  PubMed  Google Scholar 

  16. Eckhardt M, Gerardy-Schahn R (1997) Molecular cloning of the hamster CMP-sialic acid transporter. Eur J Biochem 248:187–192

    CAS  PubMed  Google Scholar 

  17. Miura N, Ishida N, Hoshino M, Yamauchi M, Hara T, Ayusawa D, Kawakita M (1996) Human UDP-galactose translocator: molecular cloning of a complementary DNA that complements the genetic defect of a mutant cell line deficient in UDP-galactose translocator. J Biochem (Tokyo) 120:236–241

    Google Scholar 

  18. Ishida N, Miura N, Yoshioka S, Kawakita M (1996) Molecular cloning and characterization of a novel isoform of the human UDP-galactose transporter, and of related complementary DNAs belonging to the nucleotide-sugar transporter gene family. J Biochem (Tokyo) 120:1074–1078

    Google Scholar 

  19. Ma DQ, Russell DG, Beverley SM, Turco SJ (1997) Golgi GDP-mannose uptake requires Leishmania LPG2: A member of a eukaryotic family of putative nucleotide-sugar transporters. J Biol Chem 272:3799–3805

    Article  CAS  PubMed  Google Scholar 

  20. Dean N, Zhang YB, Poster JB (1997) The VGR4 gene is required for GDP-mannose transport into the lumen of the Golgi in the yeast, Saccharomyces cerevisiae. J Biol Chem 272:31908–31914

    Article  CAS  PubMed  Google Scholar 

  21. Ishida N, Ito M, Yoshioka S, Sun-Wada GH, Kawakita M (1998) Functional expression of human Golgi CMP-sialic acid transporter in the Golgi complex of a transporter-deficient Chinese hamster ovary cell mutant. J Biochem (Tokyo) 124:171–178

    Google Scholar 

  22. Aoki K, Sun-Wada G-H, Segawa H, Yoshioka S, Ishida N, Kawakita M (1999) Expression and activity of chimeric molecules between human UDP-galactose transporter and CMP-sialic acid transporter. J Biochem (Tokyo) 126:940–950

    Google Scholar 

  23. Gao XD, Dean N (2000) Distinct protein domains of the yeast Golgi GDP-mannose transporter mediate oligomer assembly and export from the endoplasmic reticulum. J Biol Chem 275:17718–17727

    Article  CAS  PubMed  Google Scholar 

  24. Ishida N, Yoshioka S, Iida M, Sudo K, Miura N, Aoki K, Kawakita M (1999) Indispensability of transmembrane domains of Golgi UDP-galactose transporter as revealed by analysis of genetic defects in UDP-galactose transporter-deficient murine Had-1 mutant cell lines and construction of deletion mutants. J Biochem (Tokyo) 126:1107–1117

    Google Scholar 

  25. Abe M, Hashimoto H, Yoda K (1999) Molecular characterization of Vig4/Vrg4 GDP-mannose transporter of the yeast Saccharomyces cerevisiae. FEBS Lett 458:309–312

    Article  CAS  PubMed  Google Scholar 

  26. Aoki K, Ishida N, Kawakita M (2001) Substrate recognition by UDP-galactose and CMP-sialic acid transporters. Different sets of transmembrane helices are utilized for the specific recognition of UDP-galactose and CMP-sialic acid. J Biol Chem 276:21555–21561

    Article  CAS  PubMed  Google Scholar 

  27. Blair SS (2000) Notch signaling: fringe really is a glycosyltransferase. Curr Biol 10:R608–R612

    Article  CAS  PubMed  Google Scholar 

  28. Selva EM, Hong K, Baeg GH, Beverley SM, Turco SJ, Perrimon N, Hacker U (2001) Dual role of the fringe connection gene in both heparan sulphate and fringe-dependent signalling events. Nat Cell Biol 3:809–815

    Article  CAS  PubMed  Google Scholar 

  29. Goto S, Taniguchi M, Muraoka M, Toyoda H, Sado Y, Kawakita M, Hayashi S (2001) UDP-sugar transporter implicated in glycosylation and processing of Notch. Nat Cell Biol 3:816–822

    Article  CAS  PubMed  Google Scholar 

  30. Herman T, Horvitz HR (1999) Three proteins involved in Caenorhabditis elegans vulval invagination are similar to components of a glycosylation pathway. Proc Natl Acad Sci USA 96:974–979

    Article  CAS  PubMed  Google Scholar 

  31. Herman T, Hartwieg E, Horvitz HR (1999) sqv mutants of Caenorhabditis elegans are defective in vulval epithelial invagination. Proc Natl Acad Sci USA 96:968–973

    Article  CAS  PubMed  Google Scholar 

  32. Bulik DA, Wei G, Toyoda H, Kinoshita-Toyoda A, Waldrip WR, Esko JD, Robbins PW, Selleck SB (2000) sqv-3, -7, and -8, a set of genes affecting morphogenesis in Caenorhabditis elegans, encode enzymes required for glycosaminoglycan biosynthesis. Proc Natl Acad Sci USA 97:10838–10843

    Article  CAS  PubMed  Google Scholar 

  33. Berninsone P, Hwang HY, Zemtseva I, Horvitz HR, Hirschberg CB (2001) SQV-7, a protein involved in Caenorhabditis elegans epithelial invagination and early embryogenesis, transports UDP-glucuronic acid, UDP-N-acetylgalactosamine, and UDP-galactose. Proc Natl Acad Sci USA 98:3738–3743

    Article  CAS  PubMed  Google Scholar 

  34. Hwang HY, Horvitz HR (2002) The SQV-1 UDP-glucuronic acid decarboxylase and the SQV-7 nucleotide-sugar transporter may act in the Golgi apparatus to affect Caenorhabditis elegans vulval morphogenesis and embryonic development. Proc Natl Acad Sci USA 99:14218–14223

    Article  CAS  PubMed  Google Scholar 

  35. Okajima T, Yoshida K, Kondo T, Furukawa K (1999) Human homolog of Caenorhabditis elegans sqv-3 gene is galactosyltransferase I involved in the biosynthesis of the glycosaminoglycan-protein linkage region of proteoglycans. J Biol Chem 274:22915–22918

    Article  CAS  PubMed  Google Scholar 

  36. Okajima T, Fukumoto S, Furukawa K, Urano T (1999) Molecular basis for the progeroid variant of Ehlers-Danlos syndrome. Identification and characterization of two mutations in galactosyltransferase I gene. J Biol Chem 274:28841–28844

    Article  CAS  PubMed  Google Scholar 

  37. Almeida R, Levery SB, Mandel U, Kresse H, Schwientek T, Bennett EP, Clausen H (1999) Cloning and expression of a proteoglycan UDP-galactose:β-xylose β1,4-galactosyltransferase I. A seventh member of the human β4-galactosyltransferase gene family. J Biol Chem 274:26165–26171

    Article  CAS  PubMed  Google Scholar 

  38. Carey DJ, Sommers LW, Hirschberg CB (1980) CMP-N-acetylneuraminic acid: isolation from and penetration into mouse liver microsomes. Cell 19:597–605

    CAS  PubMed  Google Scholar 

  39. Eckhardt M, Mülenhoff M, Bethe A, Gerardy-Schahn R (1996) Expression cloning of the Golgi CMP-sialic acid transporter. Proc Natl Acad Sci USA 93:7572–7576

    Article  CAS  PubMed  Google Scholar 

  40. Sommers LW, Hirschberg CB (1982) Transport of sugar nucleotides into rat liver Golgi. A new Golgi marker activity. J Biol Chem 257:10811–10817

    CAS  PubMed  Google Scholar 

  41. Eckhardt M, Gotza B, Gerardy-Schahn R (1998) Mutants of the CMP-sialic acid transporter causing the Lec2 phenotype. J Biol Chem 273:20189–20195

    Article  CAS  PubMed  Google Scholar 

  42. Eisenberg I, Avidan N, Potikha T, Hochner H, Chen M, Olender T, Barash M, Shemesh M, Sadeh M, Grabov-Nardini G, Shmilevich I, Friedmann A, Karpati G, Bradley WG, Baumbach L, Lancet D, Asher EB, Beckmann JS, Argov Z, Mitrani-Rosenbaum S (2001) The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nat Genet 29:83–87

    Article  CAS  PubMed  Google Scholar 

  43. Brandan E, Fleischer B (1982) Orientation and role of nucleosidediphosphatase and 5′-nucleotidase in Golgi vesicles from rat liver. Biochemistry 21:4640–4645

    CAS  PubMed  Google Scholar 

  44. Hara T, Hattori S, Kawakita M (1989) Isolation and characterization of mouse FM3A cell mutants which are devoid of Newcastle disease virus receptors. J Virol 63:182–188

    CAS  PubMed  Google Scholar 

  45. Hara T, Yamauchi M, Takahashi E, Hoshino M, Aoki K, Ayusawa D, Kawakita M (1993) The UDP-galactose translocator gene is mapped to band Xp11.23-p11.22 containing the Wiskott-Aldrich syndrome locus. Somatic Cell Mol Genet 19:571–575

    CAS  PubMed  Google Scholar 

  46. Yoshioka S, Sun-Wada GH, Ishida N, Kawakita M (1997) Expression of the human UDP-galactose transporter in the Golgi membranes of murine Had-1 cells that lack the endogenous transporter. J Biochem (Tokyo) 122:691–695

    Google Scholar 

  47. Sun-Wada G-H, Yoshioka S, Ishida N, Kawakita M (1998) Functional expression of the human UDP-galactose transporters in the yeast Saccharomyces cerevisiae. J Biochem (Tokyo) 123:912–917

    Google Scholar 

  48. Segawa H, Kawakita M, Ishida N (2002) Human and Drosophila UDP-galactose transporters transport UDP-N-acetylgalactosamine in addition to UDP-galactose. Eur J Biochem 269:128–138

    Article  CAS  PubMed  Google Scholar 

  49. Kumamoto K, Goto Y, Sekikawa K, Takenoshita S, Ishida N, Kawakita M, Kannagi R (2001) Increased expression of UDP-galactose transporter messenger RNA in human colon cancer tissues and its implication in synthesis of Thomsen-Friedenreich antigen and sialyl Lewis A/X determinants. Cancer Res 61:4620–4627

    CAS  PubMed  Google Scholar 

  50. Kannagi R (1997) Carbohydrate-mediated cell adhesion involved in hematogenous metastasis of cancer. Glycoconj J 14:577–584

    Article  CAS  PubMed  Google Scholar 

  51. Perez M, Hirschberg CB (1985) Translocation of UDP-N-acetylglucosamine into vesicles derived from rat liver rough endoplasmic reticulum and Golgi apparatus. J Biol Chem 260:4671–4678

    CAS  PubMed  Google Scholar 

  52. Abeijon C, Mandon EC, Robbins PW, Hirschberg CB (1996) A mutant yeast deficient in Golgi transport of uridine diphosphate N-acetylglucosamine. J Biol Chem 271:8851–8854

    Article  CAS  PubMed  Google Scholar 

  53. Guillen E, Abeijon C, Hirschberg CB (1998) Mammalian Golgi apparatus UDP-N-acetylglucosamine transporter: molecular cloning by phenotypic correction of a yeast mutant. Proc Natl Acad Sci USA 95:7888–7892

    Article  CAS  PubMed  Google Scholar 

  54. Ishida N, Yoshioka S, Chiba Y, Takeuchi M, Kawakita M (1999) Molecular cloning and functional expression of the human Golgi UDP-N-acetylglucosamine transporter. J Biochem (Tokyo) 126:68–77

    Google Scholar 

  55. Kainuma M, Chiba Y, Takeuchi M, Jigami Y (2001) Overexpression of HUT1 gene stimulates in vivo galactosylation by enhancing UDP-galactose transport activity in Saccharomyces cerevisiae. Yeast 18:533–541

    Article  CAS  PubMed  Google Scholar 

  56. Nakanishi H, Nakayama K, Yokota A, Tachikawa H, Takahashi N, Jigami Y (2001) Hut1 proteins identified in Saccharomyces cerevisiae and Schizosaccharomyces pombe are functional homologues involved in the protein-folding process at the endoplasmic reticulum. Yeast 18:543–554

    Article  CAS  PubMed  Google Scholar 

  57. Norambuena L, Marchant L, Berninsone P, Hirschberg CB, Silva H, Orellana A (2002) Transport of UDP-galactose in plants. Identification and functional characterization of AtUTr1, an Arabidopsis thaliana UDP-galactose/UDP-glucose transporter. J Biol Chem 277:32923–32929

    Article  CAS  PubMed  Google Scholar 

  58. Etzioni A, Tonetti M (2000) Leukocyte adhesion deficiency II—from A to almost Z. Immunol Rev 178:138–147

    Article  CAS  PubMed  Google Scholar 

  59. Lübke T, Marquardt T, Figura K von, Korner C (1999) A new type of carbohydrate-deficient glycoprotein syndrome due to a decreased import of GDP-fucose into the Golgi. J Biol Chem 274:25986–25989

    Article  PubMed  Google Scholar 

  60. Sturla L, Puglielli L, Tonetti M, Berninsone P, Hirschberg CB, De Flora A, Etzioni A (2001) Impairment of the Golgi GDP-l-fucose transport and unresponsiveness to fucose replacement therapy in LAD II patients. Pediatr Res 49:537–542

    CAS  PubMed  Google Scholar 

  61. Lühn K, Wild MK, Eckhardt M, Gerardy-Schahn R, Vestweber D (2001) The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose transporter. Nat Genet 28:69–72

    Article  CAS  PubMed  Google Scholar 

  62. Lübke T, Marquardt T, Etzioni A, Hartmann E, von Figura K, Korner C (2001) Complementation cloning identifies CDG-IIc, a new type of congenital disorders of glycosylation, as a GDP-fucose transporter deficiency. Nat Genet 28:73–76

    Article  PubMed  Google Scholar 

  63. Etzioni A, Sturla L, Antonellis A, Green ED, Gershoni-Baruch R, Berninsone PM, Hirschberg CB, Tonetti M (2002) Leukocyte adhesion deficiency (LAD) type II/carbohydrate deficient glycoprotein (CDG) IIc founder effect and genotype/phenotype correlation. Am J Med Genet 110:131–135

    Article  PubMed  Google Scholar 

  64. Hirschberg CB (2001) Golgi nucleotide sugar transport and leukocyte adhesion deficiency II. J Clin Invest 108:3–6

    Article  CAS  PubMed  Google Scholar 

  65. Muraoka M, Kawakita M, Ishida N (2001) Molecular characterization of human UDP-glucuronic acid/UDP-N-acetylgalactosamine transporter, a novel nucleotide sugar transporter with dual substrate specificity. FEBS Lett 495:87–93

    Article  CAS  PubMed  Google Scholar 

  66. Briles EB (1981) Normal glycosaminoglycan production in a galactosylation-defective lectin-resistant CHO cell variant. Biochem Biophys Res Commun 103:38–45

    CAS  PubMed  Google Scholar 

  67. Toma L, Pinhal MA, Dietrich CP, Nader HB, Hirschberg CB (1996) Transport of UDP-galactose into the Golgi lumen regulates the biosynthesis of proteoglycans. J Biol Chem 271:3897–3901

    Article  CAS  PubMed  Google Scholar 

  68. Kannagi R (2002) Regulatory roles of carbohydrate ligands for selectins in the homing of lymphocytes. Curr Opin Struct Biol 12:599–608

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. Yutaka Sanai, Department of Biochemical Cell Research, Tokyo Metropolitan Institute of Medical Science for his useful discussion and encouragement.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nobuhiro Ishida.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ishida, N., Kawakita, M. Molecular physiology and pathology of the nucleotide sugar transporter family (SLC35). Pflugers Arch - Eur J Physiol 447, 768–775 (2004). https://doi.org/10.1007/s00424-003-1093-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-003-1093-0

Keywords

Navigation