Skip to main content
SpringerLink
Log in

Glycosylation of solute carriers: mechanisms and functional consequences

  • Invited Review
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Solute carriers (SLCs) are one of the largest groups of multi-spanning membrane proteins in mammals and include ubiquitously expressed proteins as well as proteins with highly restricted tissue expression. A vast number of studies have addressed the function and organization of SLCs as well as their posttranslational regulation, but only relatively little is known about the role of SLC glycosylation. Glycosylation is one of the most abundant posttranslational modifications of animal proteins and through recent advances in our understanding of protein–glycan interactions, the functional roles of SLC glycosylation are slowly emerging. The purpose of this review is to provide a concise overview of the aspects of glycobiology most relevant to SLCs, to discuss the roles of glycosylation in the regulation and function of SLCs, and to outline the major open questions in this field, which can now be addressed given major technical advances in this and related fields of study in recent years.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Aebi M, Bernasconi R, Clerc S, Molinari M (2010) N-glycan structures: recognition and processing in the ER. Trends Biochem Sci 35:74–82. doi:10.1016/j.tibs.2009.10.001

    Article  PubMed  CAS  Google Scholar 

  2. Apweiler R, Hermjakob H, Sharon N (1999) On the frequency of protein glycosylation, as deduced from analysis of the SWISS-PROT database. Biochim Biophys Acta 1473:4–8

    Article  PubMed  CAS  Google Scholar 

  3. Asada M, Furukawa K, Segawa K, Endo T, Kobata A (1997) Increased Expression of Highly Branched N-Glycans at Cell Surface Is Correlated with the Malignant Phenotypes of Mouse Tumor Cells. Cancer Res 57:1073–1080

    PubMed  CAS  Google Scholar 

  4. Asano T, Shibasaki Y, Lin JL, Tsukuda K, Katagiri H, Ishihara H, Yazaki Y, Oka Y (1991) Expression of the GLUT1 glucose transporter increases thymidine uptake in Chinese hamster ovary cells at low glucose concentrations. Cancer Res 51:4450–4454

    PubMed  CAS  Google Scholar 

  5. Asano T, Takata K, Katagiri H, Ishihara H, Inukai K, Anai M, Hirano H, Yazaki Y, Oka Y (1993) The role of N-glycosylation in the targeting and stability of GLUT1 glucose transporter. FEBS Lett 324:258–261

    Article  PubMed  CAS  Google Scholar 

  6. Azroyan A, Laghmani K, Crambert G, Mordasini D, Doucet A, Edwards A (2011) Regulation of pendrin by pH: dependence on glycosylation. Biochem J 434:61–72. doi:10.1042/BJ20101411

    Article  PubMed  CAS  Google Scholar 

  7. Balamurugan K, Said HM (2002) Functional role of specific amino acid residues in human thiamine transporter SLC19A2: mutational analysis. Am J Physiol Gastrointest Liver Physiol 283:G37–G43. doi:10.1152/ajpgi.00547.2001

    Article  PubMed  CAS  Google Scholar 

  8. Bennett ER, Kanner BI (1997) The membrane topology of GAT-1, a (Na+ + Cl-)-coupled gamma-aminobutyric acid transporter from rat brain. J Biol Chem 272:1203–1210

    Article  PubMed  CAS  Google Scholar 

  9. Bodoy S, Fotiadis D, Stoeger C, Kanai Y, Palacin M (2013) The small SLC43 family: facilitator system l amino acid transporters and the orphan EEG1. Mol Asp Med 34:638–645. doi:10.1016/j.mam.2012.12.006

    Article  CAS  Google Scholar 

  10. Bodoy S, Martin L, Zorzano A, Palacin M, Estevez R, Bertran J (2005) Identification of LAT4, a novel amino acid transporter with system L activity. J Biol Chem 280:12002–12011. doi:10.1074/jbc.M408638200

    Article  PubMed  CAS  Google Scholar 

  11. Boersema PJ, Geiger T, Wisniewski JR, Mann M (2013) Quantification of the N-glycosylated secretome by super-SILAC during breast cancer progression and in human blood samples. Mol Cell Proteomics MCP 12:158–171. doi:10.1074/mcp.M112.023614

    Article  PubMed  CAS  Google Scholar 

  12. Boscher C, Dennis JW, Nabi IR (2011) Glycosylation, galectins and cellular signaling. Curr Opin Cell Biol 23:383–392. doi:10.1016/j.ceb.2011.05.001

    Article  PubMed  CAS  Google Scholar 

  13. Boscher C, Zheng YZ, Lakshminarayan R, Johannes L, Dennis JW, Foster LJ, Nabi IR (2012) Galectin-3 protein regulates mobility of N-cadherin and GM1 ganglioside at cell-cell junctions of mammary carcinoma cells. J Biol Chem 287:32940–32952. doi:10.1074/jbc.M112.353334

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Bradford AD, Terris JM, Ecelbarger CA, Klein JD, Sands JM, Chou CL, Knepper MA (2001) 97- and 117-kDa forms of collecting duct urea transporter UT-A1 are due to different states of glycosylation. Am J Physiol Renal Physiol 281:F133–F143

    PubMed  CAS  Google Scholar 

  15. Brast S, Grabner A, Sucic S, Sitte HH, Hermann E, Pavenstadt H, Schlatter E, Ciarimboli G (2012) The cysteines of the extracellular loop are crucial for trafficking of human organic cation transporter 2 to the plasma membrane and are involved in oligomerization. FASEB J Off Publ Fed Am Soc Exp Biol 26:976–986. doi:10.1096/fj.11-180679

    CAS  Google Scholar 

  16. Chen G, Frohlich O, Yang Y, Klein JD, Sands JM (2006) Loss of N-linked glycosylation reduces urea transporter UT-A1 response to vasopressin. J Biol Chem 281:27436–27442. doi:10.1074/jbc.M605525200

    Article  PubMed  CAS  Google Scholar 

  17. Chen G, Howe AG, Xu G, Frohlich O, Klein JD, Sands JM (2011) Mature N-linked glycans facilitate UT-A1 urea transporter lipid raft compartmentalization. FASEB J Off Publ Fed Am Soc Exp Biol 25:4531–4539. doi:10.1096/fj.11-185991

    CAS  Google Scholar 

  18. Chen LM, Kelly ML, Rojas JD, Parker MD, Gill HS, Davis BA, Boron WF (2008) Use of a new polyclonal antibody to study the distribution and glycosylation of the sodium-coupled bicarbonate transporter NCBE in rodent brain. Neuroscience 151:374–385. doi:10.1016/j.neuroscience.2007.10.015

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Chen R, Jiang X, Sun D, Han G, Wang F, Ye M, Wang L, Zou H (2009) Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry. J Proteome Res 8:651–661. doi:10.1021/pr8008012

    Article  PubMed  CAS  Google Scholar 

  20. Choi I, Hu L, Rojas JD, Schmitt BM, Boron WF (2003) Role of glycosylation in the renal electrogenic Na+−HCO3- cotransporter (NBCe1). Am J Physiol Renal Physiol 284:F1199–F1206. doi:10.1152/ajprenal.00131.2002

    Article  PubMed  CAS  Google Scholar 

  21. Christiansen MN, Chik J, Lee L, Anugraham M, Abrahams JL, Packer NH (2014) Cell surface protein glycosylation in cancer. Proteomics 14:525–546. doi:10.1002/pmic.201300387

    Article  PubMed  CAS  Google Scholar 

  22. Cihlar T, Lin DC, Pritchard JB, Fuller MD, Mendel DB, Sweet DH (1999) The antiviral nucleotide analogs cidofovir and adefovir are novel substrates for human and rat renal organic anion transporter 1. Mol Pharmacol 56:570–580

    PubMed  CAS  Google Scholar 

  23. Claro da Silva T, Polli JE, Swaan PW (2013) The solute carrier family 10 (SLC10): beyond bile acid transport. Mol Asp Med 34:252–269. doi:10.1016/j.mam.2012.07.004

    Article  CAS  Google Scholar 

  24. Collins D, Winter DC, Hogan AM, Schirmer L, Baird AW, Stewart GS (2010) Differential protein abundance and function of UT-B urea transporters in human colon. Am J Physiol Gastrointest Liver Physiol 298:G345–G351. doi:10.1152/ajpgi.00405.2009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Counillon L, Pouyssegur J, Reithmeier RA (1994) The Na+/H+ exchanger NHE-1 possesses N- and O-linked glycosylation restricted to the first N-terminal extracellular domain. Biochemistry 33:10463–10469

    Article  PubMed  CAS  Google Scholar 

  26. Cruz-Muros I, Afonso-Oramas D, Abreu P, Rodriguez M, Gonzalez MC, Gonzalez-Hernandez T (2008) Deglycosylation and subcellular redistribution of VMAT2 in the mesostriatal system during normal aging. Neurobiol Aging 29:1702–1711. doi:10.1016/j.neurobiolaging.2007.04.003

    Article  PubMed  CAS  Google Scholar 

  27. Darrow AL, Shohet RV (2015) Galectin-3 deficiency exacerbates hyperglycemia and the endothelial response to diabetes. Cardiovasc Diabetol 14:73. doi:10.1186/s12933-015-0230-3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Dennis J, Laferte S, Waghorne C, Breitman M, Kerbel R (1987) Beta 1–6 branching of Asn-linked oligosaccharides is directly associated with metastasis. Science 236:582–585. doi:10.1126/science.2953071

    Article  PubMed  CAS  Google Scholar 

  29. Dennis JW, Brewer CF (2013) Density-dependent lectin-glycan interactions as a paradigm for conditional regulation by posttranslational modifications. Mol Cell Proteomics MCP 12:913–920. doi:10.1074/mcp.R112.026989

    Article  PubMed  CAS  Google Scholar 

  30. Ednie AR, Bennett ES (2012) Modulation of voltage-gated ion channels by sialylation. Compr Physiol 2:1269–1301. doi:10.1002/cphy.c110044

    PubMed  Google Scholar 

  31. Endo T, Kasahara M, Kobata A (1990) Structures of the asparagine-linked sugar chain of glucose transporter from human erythrocytes. Biochemistry 29:9126–9134

    Article  PubMed  CAS  Google Scholar 

  32. Fajka-Boja R, Blasko A, Kovacs-Solyom F, Szebeni GJ, Toth GK, Monostori E (2008) Co-localization of galectin-1 with GM1 ganglioside in the course of its clathrin- and raft-dependent endocytosis. Cell Mol Life Sci CMLS 65:2586–2593. doi:10.1007/s00018-008-8143-x

    Article  PubMed  CAS  Google Scholar 

  33. Fukuda M, Dell A, Fukuda MN (1984) Structure of fetal lactosaminoglycan. The carbohydrate moiety of Band 3 isolated from human umbilical cord erythrocytes. J Biol Chem 259:4782–4791

    PubMed  CAS  Google Scholar 

  34. Fukuda M, Dell A, Oates JE, Fukuda MN (1984) Structure of branched lactosaminoglycan, the carbohydrate moiety of band 3 isolated from adult human erythrocytes. J Biol Chem 259:8260–8273

    PubMed  CAS  Google Scholar 

  35. Groves JD, Tanner MJ (1994) Role of N-glycosylation in the expression of human band 3-mediated anion transport. Mol Membr Biol 11:31–38

    Article  PubMed  CAS  Google Scholar 

  36. Hagenbuch B, Stieger B, Foguet M, Lubbert H, Meier PJ (1991) Functional expression cloning and characterization of the hepatocyte Na+/bile acid cotransport system. Proc Natl Acad Sci U S A 88:10629–10633

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Han KH, Lee HW, Handlogten ME, Whitehill F, Osis G, Croker BP, Clapp WL, Verlander JW, Weiner ID (2013) Expression of the ammonia transporter family member, Rh B Glycoprotein, in the human kidney. Am J Physiol Renal Physiol 304:F972–F981. doi:10.1152/ajprenal.00550.2012

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Hayashi H, Yamashita Y (2012) Role of N-glycosylation in cell surface expression and protection against proteolysis of the intestinal anion exchanger SLC26A3. Am J Physiol Cell Physiol 302:C781–C795. doi:10.1152/ajpcell.00165.2011

    Article  PubMed  CAS  Google Scholar 

  39. Hayes G, Busch A, Lotscher M, Waldegger S, Lang F, Verrey F, Biber J, Murer H (1994) Role of N-linked glycosylation in rat renal Na/Pi-cotransport. J Biol Chem 269:24143–24149

    PubMed  CAS  Google Scholar 

  40. Hediger MA, Clemencon B, Burrier RE, Bruford EA (2013) The ABCs of membrane transporters in health and disease (SLC series): introduction. Mol Asp Med 34:95–107. doi:10.1016/j.mam.2012.12.009

    Article  CAS  Google Scholar 

  41. Hediger MA, Mendlein J, Lee HS, Wright EM (1991) Biosynthesis of the cloned intestinal Na+/glucose cotransporter. Biochim Biophys Acta 1064:360–364

    Article  PubMed  CAS  Google Scholar 

  42. Helenius A, Aebi M (2004) Roles of N-linked glycans in the endoplasmic reticulum. Annu Rev Biochem 73:1019–1049. doi:10.1146/annurev.biochem.73.011303.073752

    Article  PubMed  CAS  Google Scholar 

  43. Hiki K, D’Andrea RJ, Furze J, Crawford J, Woollatt E, Sutherland GR, Vadas MA, Gamble JR (1999) Cloning, characterization, and chromosomal location of a novel human K+−Cl- cotransporter. J Biol Chem 274:10661–10667

    Article  PubMed  CAS  Google Scholar 

  44. Hirayama BA, Wright EM (1992) Glycosylation of the rabbit intestinal brush border Na+/glucose cotransporter. Biochim Biophys Acta 1103:37–44

    Article  PubMed  CAS  Google Scholar 

  45. Hoover RS, Poch E, Monroy A, Vazquez N, Nishio T, Gamba G, Hebert SC (2003) N-Glycosylation at two sites critically alters thiazide binding and activity of the rat thiazide-sensitive Na(+):Cl(−) cotransporter. J Am Soc Nephrol JASN 14:271–282

    Article  PubMed  CAS  Google Scholar 

  46. Ioffe E, Stanley P (1994) Mice lacking N-acetylglucosaminyltransferase I activity die at mid-gestation, revealing an essential role for complex or hybrid N-linked carbohydrates. Proc Natl Acad Sci U S A 91:728–732

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Johnson D, Bennett ES (2008) Gating of the shaker potassium channel is modulated differentially by N-glycosylation and sialic acids. Pflugers Arch - Eur J Physiol 456:393–405. doi:10.1007/s00424-007-0378-0

    Article  CAS  Google Scholar 

  48. Johnson D, Montpetit ML, Stocker PJ, Bennett ES (2004) The sialic acid component of the beta1 subunit modulates voltage-gated sodium channel function. J Biol Chem 279:44303–44310. doi:10.1074/jbc.M408900200

    Article  PubMed  CAS  Google Scholar 

  49. Kim D, Sands JM, Klein JD (2003) Changes in renal medullary transport proteins during uncontrolled diabetes mellitus in rats. Am J Physiol Renal Physiol 285:F303–F309. doi:10.1152/ajprenal.00438.2002

    Article  PubMed  CAS  Google Scholar 

  50. Kinjo TG, Szerencsei RT, Winkfein RJ, Kang K, Schnetkamp PP (2003) Topology of the retinal cone NCKX2 Na/Ca-K exchanger. Biochemistry 42:2485–2491. doi:10.1021/bi0270788

    Article  PubMed  CAS  Google Scholar 

  51. Kleene R, Schachner M (2004) Glycans and neural cell interactions. Nat Rev Neurosci 5:195–208. doi:10.1038/nrn1349

    Article  PubMed  CAS  Google Scholar 

  52. Kornfeld R, Kornfeld S (1985) Assembly of asparagine-linked oligosaccharides. Annu Rev Biochem 54:631–664. doi:10.1146/annurev.bi.54.070185.003215

    Article  PubMed  CAS  Google Scholar 

  53. Lakshminarayan R, Wunder C, Becken U, Howes MT, Benzing C, Arumugam S, Sales S, Ariotti N, Chambon V, Lamaze C, Loew D, Shevchenko A, Gaus K, Parton RG, Johannes L (2014) Galectin-3 drives glycosphingolipid-dependent biogenesis of clathrin-independent carriers. Nat Cell Biol 16:595–606. doi:10.1038/ncb2970

    Article  PubMed  CAS  Google Scholar 

  54. Landolt-Marticorena C, Charuk JH, Reithmeier RA (1998) Two glycoprotein populations of band 3 dimers are present in human erythrocytes. Mol Membr Biol 15:153–158

    Article  PubMed  CAS  Google Scholar 

  55. Lau KS, Partridge EA, Grigorian A, Silvescu CI, Reinhold VN, Demetriou M, Dennis JW (2007) Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation. Cell 129:123–134. doi:10.1016/j.cell.2007.01.049

    Article  PubMed  CAS  Google Scholar 

  56. Levy O, De la Vieja A, Ginter CS, Riedel C, Dai G, Carrasco N (1998) N-linked glycosylation of the thyroid Na+/I- symporter (NIS). Implications for its secondary structure model. J Biol Chem 273:22657–22663

    Article  PubMed  CAS  Google Scholar 

  57. Levy Y, Arbel-Goren R, Hadari YR, Eshhar S, Ronen D, Elhanany E, Geiger B, Zick Y (2001) Galectin-8 Functions as a Matricellular Modulator of Cell Adhesion. J Biol Chem 276:31285–31295. doi:10.1074/jbc.M100340200

    Article  PubMed  CAS  Google Scholar 

  58. Li J, Quilty J, Popov M, Reithmeier RA (2000) Processing of N-linked oligosaccharide depends on its location in the anion exchanger, AE1, membrane glycoprotein. Biochem J 349:51–57

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Lipkowitz MS, Leal-Pinto E, Cohen BE, Abramson RG (2004) Galectin 9 is the sugar-regulated urate transporter/channel UAT. Glycoconj J 19:491–498. doi:10.1023/B:GLYC.0000014078.65610.2f

    Article  PubMed  Google Scholar 

  60. Liu F-T, Rabinovich GA (2005) Galectins as modulators of tumour progression. Nat Rev Cancer 5:29–41

    Article  PubMed  CAS  Google Scholar 

  61. Liu Z, Chen Y, Mo R, Hui C, Cheng JF, Mohandas N, Huang CH (2000) Characterization of human RhCG and mouse Rhcg as novel nonerythroid Rh glycoprotein homologues predominantly expressed in kidney and testis. J Biol Chem 275:25641–25651. doi:10.1074/jbc.M003353200

    Article  PubMed  CAS  Google Scholar 

  62. Mangravite LM, Giacomini KM (2003) Sorting of rat SPNT in renal epithelium is independent of N-glycosylation. Pharm Res 20:319–323

    Article  PubMed  CAS  Google Scholar 

  63. Martinez-Maza R, Poyatos I, Lopez-Corcuera B, Nu E, Gimenez C, Zafra F, Aragon C (2001) The role of N-glycosylation in transport to the plasma membrane and sorting of the neuronal glycine transporter GLYT2. J Biol Chem 276:2168–2173. doi:10.1074/jbc.M006774200

    Article  PubMed  CAS  Google Scholar 

  64. Matus A, De Petris S, Raff MC (1973) Mobility of concanavalin A receptors in myelin and synaptic membranes. Nat New Biol 244:278–280

    Article  PubMed  CAS  Google Scholar 

  65. Mazumder R, Morampudi KS, Motwani M, Vasudevan S, Goldman R (2012) Proteome-wide analysis of single-nucleotide variations in the N-glycosylation sequon of human genes. PLoS One 7:e36212. doi:10.1371/journal.pone.0036212

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Medzihradszky KF, Kaasik K, Chalkley RJ (2015) Tissue-specific glycosylation at the glycopeptide level. Mol Cell Proteomics MCP 14:2103–2110. doi:10.1074/mcp.M115.050393

    Article  PubMed  CAS  Google Scholar 

  67. Meflah K, Bernard S, Massoulie J (1984) Interactions with lectins indicate differences in the carbohydrate composition of the membrane-bound enzymes acetylcholinesterase and 5'-nucleotidase in different cell types. Biochimie 66:59–69

    Article  PubMed  CAS  Google Scholar 

  68. Melikian HE, Ramamoorthy S, Tate CG, Blakely RD (1996) Inability to N-glycosylate the human norepinephrine transporter reduces protein stability, surface trafficking, and transport activity but not ligand recognition. Mol Pharmacol 50:266–276

    PubMed  CAS  Google Scholar 

  69. Mollinedo F, Gajate C (2015) Lipid rafts as major platforms for signaling regulation in cancer. Adv Biol Regul 57:130–146. doi:10.1016/j.jbior.2014.10.003

    Article  PubMed  CAS  Google Scholar 

  70. Mueckler M, Caruso C, Baldwin SA, Panico M, Blench I, Morris HR, Allard WJ, Lienhard GE, Lodish HF (1985) Sequence and structure of a human glucose transporter. Science 229:941–945

    Article  PubMed  CAS  Google Scholar 

  71. Muthusamy S, Malhotra P, Hosameddin M, Dudeja AK, Borthakur S, Saksena S, Gill RK, Dudeja PK, Alrefai WA (2015) N-glycosylation is essential for ileal ASBT function and protection against proteases. Am J Physiol Cell Physiol 308:C964–C971. doi:10.1152/ajpcell.00023.2015

    Article  PubMed  CAS  Google Scholar 

  72. Nabi IR, Shankar J, Dennis JW (2015) The galectin lattice at a glance. J Cell Sci. doi:10.1242/jcs.151159

    Google Scholar 

  73. Nakano M, Kakehi K, Tsai MH, Lee YC (2004) Detailed structural features of glycan chains derived from alpha1-acid glycoproteins of several different animals: the presence of hypersialylated, O-acetylated sialic acids but not disialyl residues. Glycobiology 14:431–441. doi:10.1093/glycob/cwh034

    Article  PubMed  CAS  Google Scholar 

  74. Nguyen TT, Amara SG (1996) N-linked oligosaccharides are required for cell surface expression of the norepinephrine transporter but do not influence substrate or inhibitor recognition. J Neurochem 67:645–655

    Article  PubMed  CAS  Google Scholar 

  75. Ochieng J, Furtak V, Lukyanov P (2002) Extracellular functions of galectin-3. Glycoconj J 19:527–535. doi:10.1023/B:GLYC.0000014082.99675.2f

    Article  CAS  Google Scholar 

  76. Ohtsubo K, Chen MZ, Olefsky JM, Marth JD (2011) Pathway to diabetes through attenuation of pancreatic beta cell glycosylation and glucose transport. Nat Med 17:1067–1075. doi:10.1038/nm.2414

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Ohtsubo K, Takamatsu S, Gao C, Korekane H, Kurosawa TM, Taniguchi N (2013) N-Glycosylation modulates the membrane sub-domain distribution and activity of glucose transporter 2 in pancreatic beta cells. Biochem Biophys Res Commun 434:346–351. doi:10.1016/j.bbrc.2013.03.076

    Article  PubMed  CAS  Google Scholar 

  78. Ohtsubo K, Takamatsu S, Minowa MT, Yoshida A, Takeuchi M, Marth JD (2005) Dietary and genetic control of glucose transporter 2 glycosylation promotes insulin secretion in suppressing diabetes. Cell 123:1307–1321. doi:10.1016/j.cell.2005.09.041

    Article  PubMed  CAS  Google Scholar 

  79. Olivares L, Aragon C, Gimenez C, Zafra F (1995) The role of N-glycosylation in the targeting and activity of the GLYT1 glycine transporter. J Biol Chem 270:9437–9442

    Article  PubMed  CAS  Google Scholar 

  80. Paredes A, Plata C, Rivera M, Moreno E, Vazquez N, Munoz-Clares R, Hebert SC, Gamba G (2006) Activity of the renal Na+−K+−2Cl- cotransporter is reduced by mutagenesis of N-glycosylation sites: role for protein surface charge in Cl- transport. Am J Physiol Renal Physiol 290:F1094–F1102. doi:10.1152/ajprenal.00071.2005

    Article  PubMed  CAS  Google Scholar 

  81. Parekh RB, Tse AG, Dwek RA, Williams AF, Rademacher TW (1987) Tissue-specific N-glycosylation, site-specific oligosaccharide patterns and lentil lectin recognition of rat Thy-1. EMBO J 6:1233–1244

    PubMed  PubMed Central  CAS  Google Scholar 

  82. Parker BL, Thaysen-Andersen M, Solis N, Scott NE, Larsen MR, Graham ME, Packer NH, Cordwell SJ (2013) Site-specific glycan-peptide analysis for determination of N-glycoproteome heterogeneity. J Proteome Res 12:5791–5800. doi:10.1021/pr400783j

    Article  PubMed  CAS  Google Scholar 

  83. Partridge EA, Le Roy C, Di Guglielmo GM, Pawling J, Cheung P, Granovsky M, Nabi IR, Wrana JL, Dennis JW (2004) Regulation of Cytokine Receptors by Golgi N-Glycan Processing and Endocytosis. Science 306:120–124. doi:10.1126/science.1102109

    Article  PubMed  CAS  Google Scholar 

  84. Pech V, Klein JD, Kozlowski SD, Wall SM, Sands JM (2005) Vasopressin increases urea permeability in the initial IMCD from diabetic rats. Am J Physiol Renal Physiol 289:F531–F535. doi:10.1152/ajprenal.00125.2005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Popov M, Tam LY, Li J, Reithmeier RA (1997) Mapping the ends of transmembrane segments in a polytopic membrane protein. Scanning N-glycosylation mutagenesis of extracytosolic loops in the anion exchanger, band 3. J Biol Chem 272:18325–18332

    Article  PubMed  CAS  Google Scholar 

  86. Rabinovich GA, Toscano MA (2009) Turning 'sweet' on immunity: galectin-glycan interactions in immune tolerance and inflammation. Nat Rev Immunol 9:338–352, http://www.nature.com/nri/journal/v9/n5/suppinfo/nri2536_S1.html

    Article  PubMed  CAS  Google Scholar 

  87. Radhakrishnan P, Dabelsteen S, Madsen FB, Francavilla C, Kopp KL, Steentoft C, Vakhrushev SY, Olsen JV, Hansen L, Bennett EP, Woetmann A, Yin G, Chen L, Song H, Bak M, Hlady RA, Peters SL, Opavsky R, Thode C, Qvortrup K, Schjoldager KT, Clausen H, Hollingsworth MA, Wandall HH (2014) Immature truncated O-glycophenotype of cancer directly induces oncogenic features. Proc Natl Acad Sci U S A 111:E4066–E4075. doi:10.1073/pnas.1406619111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Regeer RR, Nicke A, Markovich D (2007) Quaternary structure and apical membrane sorting of the mammalian NaSi-1 sulfate transporter in renal cell lines. Int J Biochem Cell Biol 39:2240–2251. doi:10.1016/j.biocel.2007.06.015

    Article  PubMed  CAS  Google Scholar 

  89. Ruhaak LR, Uh HW, Deelder AM, Dolhain RE, Wuhrer M (2014) Total plasma N-glycome changes during pregnancy. J Proteome Res 13:1657–1668. doi:10.1021/pr401128j

    Article  PubMed  CAS  Google Scholar 

  90. Salaun C, Rodrigues P, Heard JM (2001) Transmembrane topology of PiT-2, a phosphate transporter-retrovirus receptor. J Virol 75:5584–5592. doi:10.1128/JVI.75.12.5584-5592.2001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Sato S, Burdett I, Hughes RC (1993) Secretion of the baby hamster kidney 30-kDa galactose-binding lectin from polarized and nonpolarized cells: a pathway independent of the endoplasmic reticulum-golgi complex. Exp Cell Res 207:8–18. doi:10.1006/excr.1993.1157

    Article  PubMed  CAS  Google Scholar 

  92. Sato Y, Isaji T, Tajiri M, Yoshida-Yamamoto S, Yoshinaka T, Somehara T, Fukuda T, Wada Y, Gu J (2009) An N-Glycosylation Site on theβ-Propeller Domain of the Integrin α5 Subunit Plays Key Roles in Both Its Function and Site-specific Modification byβ1,4-N-Acetylglucosaminyltransferase III. J Biol Chem 284:11873–11881. doi:10.1074/jbc.M807660200

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Savalas LR, Gasnier B, Damme M, Lubke T, Wrocklage C, Debacker C, Jezegou A, Reinheckel T, Hasilik A, Saftig P, Schroder B (2011) Disrupted in renal carcinoma 2 (DIRC2), a novel transporter of the lysosomal membrane, is proteolytically processed by cathepsin L. Biochem J 439:113–128. doi:10.1042/BJ20110166

    Article  PubMed  CAS  Google Scholar 

  94. Schwetz TA, Norring SA, Bennett ES (2010) N-glycans modulate K(v)1.5 gating but have no effect on K(v)1.4 gating. Biochim Biophys Acta 1798:367–375. doi:10.1016/j.bbamem.2009.11.018

    Article  PubMed  CAS  Google Scholar 

  95. Sealover NR, Davis AM, Brooks JK, George HJ, Kayser KJ, Lin N (2013) Engineering Chinese Hamster Ovary (CHO) cells for producing recombinant proteins with simple glycoforms by zinc-finger nuclease (ZFN)-mediated gene knockout of mannosyl (alpha-1,3-)-glycoprotein beta-1,2-N-acetylglucosaminyltransferase (Mgat1). J Biotechnol 167:24–32. doi:10.1016/j.jbiotec.2013.06.006

    Article  PubMed  CAS  Google Scholar 

  96. Shamir ER, Ewald AJ (2014) Three-dimensional organotypic culture: experimental models of mammalian biology and disease. Nat Rev Mol Cell Biol 15:647–664. doi:10.1038/nrm3873

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Shayakul C, Clemencon B, Hediger MA (2013) The urea transporter family (SLC14): physiological, pathological and structural aspects. Mol Asp Med 34:313–322. doi:10.1016/j.mam.2012.12.003

    Article  CAS  Google Scholar 

  98. Shi Q, Padmanabhan R, Villegas CJ, Gu S, Jiang JX (2011) Membrane topological structure of neutral system N/A amino acid transporter 4 (SNAT4) protein. J Biol Chem 286:38086–38094. doi:10.1074/jbc.M111.220277

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Stanley P (2014) Galectins CLIC cargo inside. Nat Cell Biol 16:506–507. doi:10.1038/ncb2983

    Article  PubMed  CAS  Google Scholar 

  100. Stanley P, Cummings RD (2009) Structures Common to Different Glycans. In: Varki A, Cummings RD, Esko JD et al (eds) Essentials of Glycobiology, 2nd edn. Cold Spring Harbor (NY)

  101. Stanley P, Schachter H, Taniguchi N (2009) N-Glycans. In: Varki A, Cummings RD, Esko JD et al (eds) Essentials of Glycobiology, 2nd edn. Cold Spring Harbor (NY)

  102. Steentoft C, Bennett EP, Schjoldager KT, Vakhrushev SY, Wandall HH, Clausen H (2014) Precision genome editing: a small revolution for glycobiology. Glycobiology 24:663–680. doi:10.1093/glycob/cwu046

    Article  PubMed  CAS  Google Scholar 

  103. Steentoft C, Vakhrushev SY, Joshi HJ, Kong Y, Vester-Christensen MB, Schjoldager KT, Lavrsen K, Dabelsteen S, Pedersen NB, Marcos-Silva L, Gupta R, Bennett EP, Mandel U, Brunak S, Wandall HH, Levery SB, Clausen H (2013) Precision mapping of the human O-GalNAc glycoproteome through SimpleCell technology. EMBO J 32:1478–1488. doi:10.1038/emboj.2013.79

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Su H, Carter CB, Frohlich O, Cummings RD, Chen G (2012) Glycoforms of UT-A3 urea transporter with poly-N-acetyllactosamine glycosylation have enhanced transport activity. Am J Physiol Renal Physiol 303:F201–F208. doi:10.1152/ajprenal.00140.2012

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Subramanian VS, Marchant JS, Reidling JC, Said HM (2008) N-Glycosylation is required for Na+−dependent vitamin C transporter functionality. Biochem Biophys Res Commun 374:123–127. doi:10.1016/j.bbrc.2008.06.120

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Suzuki O, Abe M (2014) Galectin-1-mediated cell adhesion, invasion and cell death in human anaplastic large cell lymphoma: regulatory roles of cell surface glycans. Int J Oncol 44:1433–1442. doi:10.3892/ijo.2014.2319

    PubMed  PubMed Central  CAS  Google Scholar 

  107. Tabuchi M, Tanaka N, Nishida-Kitayama J, Ohno H, Kishi F (2002) Alternative splicing regulates the subcellular localization of divalent metal transporter 1 isoforms. Mol Biol Cell 13:4371–4387. doi:10.1091/mbc.E02-03-0165

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Tan Z, Lu W, Li X, Yang G, Guo J, Yu H, Li Z, Guan F (2014) Altered N-Glycan expression profile in epithelial-to-mesenchymal transition of NMuMG cells revealed by an integrated strategy using mass spectrometry and glycogene and lectin microarray analysis. J Proteome Res 13:2783–2795. doi:10.1021/pr401185z

    Article  PubMed  CAS  Google Scholar 

  109. Tanaka K, Xu W, Zhou F, You G (2004) Role of glycosylation in the organic anion transporter OAT1. J Biol Chem 279:14961–14966. doi:10.1074/jbc.M400197200

    Article  PubMed  CAS  Google Scholar 

  110. Taylor KM, Morgan HE, Johnson A, Nicholson RI (2005) Structure-function analysis of a novel member of the LIV-1 subfamily of zinc transporters, ZIP14. FEBS Lett 579:427–432. doi:10.1016/j.febslet.2004.12.006

    Article  PubMed  CAS  Google Scholar 

  111. Thorens B, Gerard N, Deriaz N (1993) GLUT2 surface expression and intracellular transport via the constitutive pathway in pancreatic beta cells and insulinoma: evidence for a block in trans-Golgi network exit by brefeldin A. J Cell Biol 123:1687–1694

    Article  PubMed  CAS  Google Scholar 

  112. Thurston TLM, Wandel MP, von Muhlinen N, Foeglein A, Randow F (2012) Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. Nature 482:414–418, http://www.nature.com/nature/journal/v482/n7385/abs/nature10744.html#supplementary-information

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Timmer RT, Klein JD, Bagnasco SM, Doran JJ, Verlander JW, Gunn RB, Sands JM (2001) Localization of the urea transporter UT-B protein in human and rat erythrocytes and tissues. Am J Physiol Cell Physiol 281:C1318–C1325

    PubMed  CAS  Google Scholar 

  114. Toscano MA, Bianco GA, Ilarregui JM, Croci DO, Correale J, Hernandez JD, Zwirner NW, Poirier F, Riley EM, Baum LG, Rabinovich GA (2007) Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death. Nat Immunol 8:825–834, http://www.nature.com/ni/journal/v8/n8/suppinfo/ni1482_S1.html

    Article  PubMed  CAS  Google Scholar 

  115. Tse CM, Levine SA, Yun CH, Khurana S, Donowitz M (1994) Na+/H+ exchanger-2 is an O-linked but not an N-linked sialoglycoprotein. Biochemistry 33:12954–12961

    Article  PubMed  CAS  Google Scholar 

  116. Tsuji T, Irimura T, Osawa T (1980) The carbohydrate moiety of band-3 glycoprotein of human erythrocyte membranes. Biochem J 187:677–686

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Tsuji T, Irimura T, Osawa T (1981) The carbohydrate moiety of band 3 glycoprotein of human erythrocyte membranes. Structures of lower molecular weight oligosaccharides. J Biol Chem 256:10497–10502

    PubMed  CAS  Google Scholar 

  118. Turk E, Kerner CJ, Lostao MP, Wright EM (1996) Membrane topology of the human Na+/glucose cotransporter SGLT1. J Biol Chem 271:1925–1934

    Article  PubMed  CAS  Google Scholar 

  119. Uldry M, Ibberson M, Horisberger JD, Chatton JY, Riederer BM, Thorens B (2001) Identification of a mammalian H(+)-myo-inositol symporter expressed predominantly in the brain. EMBO J 20:4467–4477. doi:10.1093/emboj/20.16.4467

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Unal ES, Zhao R, Qiu A, Goldman ID (2008) N-linked glycosylation and its impact on the electrophoretic mobility and function of the human proton-coupled folate transporter (HsPCFT). Biochim Biophys Acta 1778:1407–1414. doi:10.1016/j.bbamem.2008.03.009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Vagin O, Kraut JA, Sachs G (2009) Role of N-glycosylation in trafficking of apical membrane proteins in epithelia. Am J Physiol Renal Physiol 296:F459–F469. doi:10.1152/ajprenal.90340.2008

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. van Geest M, Lolkema JS (2000) Membrane topology and insertion of membrane proteins: search for topogenic signals. Microbiol Mol Biol Rev MMBR 64:13–33

    Article  PubMed  Google Scholar 

  123. van Kooyk Y, Rabinovich GA (2008) Protein-glycan interactions in the control of innate and adaptive immune responses. Nat Immunol 9:593–601, http://www.nature.com/ni/journal/v9/n6/suppinfo/ni.f.203_S1.html

    Article  PubMed  CAS  Google Scholar 

  124. Varoqui H, Meunier FM, Meunier FA, Molgo J, Berrard S, Cervini R, Mallet J, Israel M, Diebler MF (1996) Expression of the vesicular acetylcholine transporter in mammalian cells. Prog Brain Res 109:83–95

    Article  PubMed  CAS  Google Scholar 

  125. Vasta GR (2009) Roles of galectins in infection. Nat Rev Micro 7:424–438, http://www.nature.com/nrmicro/journal/v7/n6/suppinfo/nrmicro2146_S1.html

    Article  CAS  Google Scholar 

  126. Velho AM, Jarvis SM (2009) Topological studies of hSVCT1, the human sodium-dependent vitamin C transporter and the influence of N-glycosylation on its intracellular targeting. Exp Cell Res 315:2312–2321. doi:10.1016/j.yexcr.2009.04.007

    Article  PubMed  CAS  Google Scholar 

  127. Vickers MF, Mani RS, Sundaram M, Hogue DL, Young JD, Baldwin SA, Cass CE (1999) Functional production and reconstitution of the human equilibrative nucleoside transporter (hENT1) in Saccharomyces cerevisiae. Interaction of inhibitors of nucleoside transport with recombinant hENT1 and a glycosylation-defective derivative (hENT1/N48Q). Biochem J 339(Pt 1):21–32

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Vogt G, Vogt B, Chuzhanova N, Julenius K, Cooper DN, Casanova JL (2007) Gain-of-glycosylation mutations. Curr Opin Genet Dev 17:245–251. doi:10.1016/j.gde.2007.04.008

    Article  PubMed  CAS  Google Scholar 

  129. Wang F, Kim BE, Dufner-Beattie J, Petris MJ, Andrews G, Eide DJ (2004) Acrodermatitis enteropathica mutations affect transport activity, localization and zinc-responsive trafficking of the mouse ZIP4 zinc transporter. Hum Mol Genet 13:563–571. doi:10.1093/hmg/ddh049

    Article  PubMed  CAS  Google Scholar 

  130. Ward JL, Leung GP, Toan SV, Tse CM (2003) Functional analysis of site-directed glycosylation mutants of the human equilibrative nucleoside transporter-2. Arch Biochem Biophys 411:19–26

    Article  PubMed  CAS  Google Scholar 

  131. Wollscheid B, Bausch-Fluck D, Henderson C, O’Brien R, Bibel M, Schiess R, Aebersold R, Watts JD (2009) Mass-spectrometric identification and relative quantification of N-linked cell surface glycoproteins. Nat Biotechnol 27:378–386. doi:10.1038/nbt.1532

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Wong SC, Zhang L, Proefke SA, Matherly LH (1998) Effects of the loss of capacity for N-glycosylation on the transport activity and cellular localization of the human reduced folate carrier. Biochim Biophys Acta 1375:6–12

    Article  PubMed  CAS  Google Scholar 

  133. Yao J, Erickson JD, Hersh LB (2004) Protein kinase A affects trafficking of the vesicular monoamine transporters in PC12 cells. Traffic 5:1006–1016. doi:10.1111/j.1600-0854.2004.00240.x

    Article  PubMed  CAS  Google Scholar 

  134. Yao J, Hersh LB (2007) The vesicular monoamine transporter 2 contains trafficking signals in both its N-glycosylation and C-terminal domains. J Neurochem 100:1387–1396. doi:10.1111/j.1471-4159.2006.04326.x

    Article  PubMed  CAS  Google Scholar 

  135. Zhang EY, Phelps MA, Banerjee A, Khantwal CM, Chang C, Helsper F, Swaan PW (2004) Topology scanning and putative three-dimensional structure of the extracellular binding domains of the apical sodium-dependent bile acid transporter (SLC10A2). Biochemistry 43:11380–11392. doi:10.1021/bi049270a

    Article  PubMed  CAS  Google Scholar 

  136. Zhao R, Goldman ID (2013) Folate and thiamine transporters mediated by facilitative carriers (SLC19A1-3 and SLC46A1) and folate receptors. Mol Asp Med 34:373–385. doi:10.1016/j.mam.2012.07.006

    Article  CAS  Google Scholar 

  137. Zhou F, Xu W, Hong M, Pan Z, Sinko PJ, Ma J, You G (2005) The role of N-linked glycosylation in protein folding, membrane targeting, and substrate binding of human organic anion transporter hOAT4. Mol Pharmacol 67:868–876. doi:10.1124/mol.104.007583

    Article  PubMed  CAS  Google Scholar 

  138. Zick Y, Eisenstein M, Goren R, Hadari Y, Levy Y, Ronen D (2002) Role of galectin-8 as a modulator of cell adhesion and cell growth. Glycoconj J 19:517–526. doi:10.1023/B:GLYC.0000014081.55445.af

    Article  CAS  Google Scholar 

  139. Zolotarev AS, Townsend RR, Stuart-Tilley A, Alper SL (1996) HCO3(−)-dependent conformational change in gastric parietal cell AE2, a glycoprotein naturally lacking sialic acid. Am J Physiol 271:G311–G321

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was support by a Carlsberg Foundation postdoctoral fellowship to NB Pedersen.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Section of Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen O, Denmark

    Nis Borbye Pedersen & Stine Falsig Pedersen

  2. Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark

    Michael C. Carlsson

Authors
  1. Nis Borbye Pedersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael C. Carlsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stine Falsig Pedersen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nis Borbye Pedersen.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pedersen, N.B., Carlsson, M.C. & Pedersen, S.F. Glycosylation of solute carriers: mechanisms and functional consequences. Pflugers Arch - Eur J Physiol 468, 159–176 (2016). https://doi.org/10.1007/s00424-015-1730-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-015-1730-4

Keywords

Search

Navigation