Vol 70, No 1 (2019)
Review paper
Published online: 2019-02-22

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Glycosylation of thyroid-stimulating hormone receptor [Glikozylacja receptora hormonu tyreotropowego]

Paulina Korta1, Ewa Pocheć1
Pubmed: 30843179
Endokrynol Pol 2019;70(1):86-100.


Thyroid-stimulating hormone receptor (TSHR) is a typical membrane receptor with 7-transmembrane helix domain (7TMR), coupled to the G protein. The mature receptor, present in the cell membrane, is composed of the A subunit comprising a large extracellular domain, and the B subunit, which consists of a short extracellular fragment anchored in the cell membrane and an intracellular part. The TSH receptor is subject to numerous post-translational modifications that determine its final structure and significantly affect its activity. One of them is glycosylation. TSHR is abundantly N-glycosylated, due to the presence of six N-glycosylation sites in the extracellular domain (Asn77, Asn99, Asn113, Asn177, Asn198, Asn302), mostly evolutionarily conserved. N-glycans constitute 30–40% of the receptor molecular weight. The glycans are necessary for the receptor trafficking to the plasma membrane and binding of TSH to the receptor. Fucosylated and sialylated N-oligosaccharides were found on TSHR molecules. The increased sialylation of TSHR glycans correlates positively with the receptor binding ability and prolongs the time of receptor incorporation into the cell membrane. TSHR is the main autoantigen in Graves’ disease (GD), one of the thyroid autoimmune diseases. One hypothesis assumes that the higher N-glycosylation of THSR in human compared to animals influences the breaking of autotolerance and GD development. N-oligosaccharides are the important part of THSR molecule, necessary for the proper functioning of receptors and probably involved in thyroid autoimmunity in GD.

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  1. Arey BJ. The Role of in Receptor Signaling. In: Petrescu S. ed. Glycosylation. InTech, London 2012: 273–286.
  2. Kim PJ, Lee DY, Jeong H. Centralized modularity of N-linked glycosylation pathways in mammalian cells. PLoS One. 2009; 4(10): e7317.
  3. Krześlak A, Jóźwiak P, Lipińska A. Glycosylation and glycoproteins in thyroid cancer: a potential role for diagnostics. In: Fahey TJ. ed. Updates in the Understanding and Management of Thyroid Cancer. InTech, London 2012: 90.
  4. Varki A. Biological roles of glycans. Glycobiology. 2017; 27(1): 3–49.
  5. Kursawe R, Paschke R. Modulation of TSHR signaling by posttranslational modifications. Trends Endocrinol Metab. 2007; 18(5): 199–207.
  6. Ohtsubo K, Marth JD. Glycosylation in cellular mechanisms of health and disease. Cell. 2006; 126(5): 855–867.
  7. Taylor ME, Drickamer K. Introduction to Glycobiology. Oxford University Press, New York 2011.
  8. Nettleship JE. Structural Biology of Glycoproteins. In: Petrescu S. ed. Glycosylation. InTech, London 2012: 41–62.
  9. Stanley P, Taniguchi N, Aebi M. N-Glycans. In: Varki A, Cummings RD, Esko JD. ed. Essentials of Glycobiology. 3rd ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor (NY) 2017.
  10. Kozłowska K, Rydlewska M, Ząbczyńska M, et al. Glikozylacja IgG w chorobach autoimmunizacyjnych. Postepy Hig Med Dosw. 2018; 72: 975–990.
  11. Surman M, Janik M. Regulacja procesu glikozylacji białek przez kaskadę cAMP. Post Biochem. 2014; 60: 305–312.
  12. Weerapana E, Imperiali B. Asparagine-linked protein glycosylation: from eukaryotic to prokaryotic systems. Glycobiology. 2006; 16(6): 91R–91101R.
  13. Moremen KW, Tiemeyer M, Nairn AV. Vertebrate protein glycosylation: diversity, synthesis and function. Nat Rev Mol Cell Biol. 2012; 13(7): 448–462.
  14. Caramelo JJ, Parodi AJ. A sweet code for glycoprotein folding. FEBS Lett. 2015; 589(22): 3379–3387.
  15. Harada Y, Hirayama H, Suzuki T. Generation and degradation of free asparagine-linked glycans. Cell Mol Life Sci. 2015; 72(13): 2509–2533.
  16. Ząbczyńska M, Pocheć E. Rola glikozylacji białek układu odpornościowego. Postepy Bioch. 2015; 61(2): 129–137.
  17. Trombetta ES. The contribution of N-glycans and their processing in the endoplasmic reticulum to glycoprotein biosynthesis. Glycobiology. 2003; 13(9): 77R–91R.
  18. Schwarz F, Aebi M. Mechanisms and principles of N-linked protein glycosylation. Curr Opin Struct Biol. 2011; 21(5): 576–582.
  19. Davies TF, Ando T, Lin RY, et al. Thyrotropin receptor-associated diseases: from adenomata to Graves disease. J Clin Invest. 2005; 115(8): 1972–1983.
  20. Núñez Miguel R, Sanders J, Furmaniak J, et al. Structure and activation of the TSH receptor transmembrane domain. Auto Immun Highlights. 2017; 8(1): 2.
  21. Iosco C, Rhoden KJ. TSHR (thyroid stimulating hormone receptor). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(9): 846–852.
  22. Rapoport B, Chazenbalk GD, Jaume JC, et al. The thyrotropin (TSH) receptor: interaction with TSH and autoantibodies. Endocr Rev. 1998; 19(6): 673–716.
  23. Chistiakov DA. Thyroid-stimulating hormone receptor and its role in Graves' disease. Mol Genet Metab. 2003; 80(4): 377–388.
  24. Yen PM. Physiological and molecular basis of thyroid hormone action. Physiol Rev. 2001; 81(3): 1097–1142.
  25. Szkudlinski MW, Fremont V, Ronin C, et al. Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships. Physiol Rev. 2002; 82(2): 473–502.
  26. Rapoport B, McLachlan SM. Thyroid Autoantibodies in Graves’ Disease. In: Rapoport B, McLachlan SM. ed. Graves’ Disease. Endocrine Updates. Vol 6. Springer, Boston 2000.
  27. Adler G. Posttranslacyjne modyfikacje receptora tyreotropiny a choroby tarczycy [The posttranslational modification of thyrotropin receptor and thyroid diseases]. Endokrynol Pol. 2005; 56(1): 72–77.
  28. Seals DF, Courtneidge SA. The ADAMs family of metalloproteases: multidomain proteins with multiple functions. Genes Dev. 2003; 17(1): 7–30.
  29. Rapoport B, McLachlan SM. TSH Receptor Cleavage Into Subunits and Shedding of the A-Subunit; A Molecular and Clinical Perspective. Endocr Rev. 2016; 37(2): 114–137.
  30. Nussey S, Whitehead S. The thyroid gland. In: Endocrinology: an integrated approach. BIOS Scientific Publishers, London 2001.
  31. Sorisky A, Gagnon A. Freedom of expression beyond the thyroid: the thyroid-stimulating hormone receptor in the adipocyte. OA Biochemistry. 2014; 2(1): 2.
  32. Andrejko M, Mizerska-Kowalska M, Zdzisińska B. Receptory związane z białkami G w odporności wrodzonej bezkręgowców. Kosmos. 2017; 66(4): 553–562.
  33. Davies T, Marians R, Latif R. The TSH receptor reveals itself. J Clin Invest. 2002; 110(2): 161–164.
  34. Tuncel M. Thyroid Stimulating Hormone Receptor. Mol Imaging Radionucl Ther. 2017; 26(Suppl _1): 87–91.
  35. Lyu J, Imachi H, Yoshimoto T, et al. Thyroid stimulating hormone stimulates the expression of glucose transporter 2 via its receptor in pancreatic beta cell line, INS-1 cells. Sci Rep. 2018; 8(1): 1986.
  36. Zhou L, Wu K, Zhang L, et al. Liver-specific deletion of TSHR inhibits hepatic lipid accumulation in mice. Biochem Biophys Res Commun. 2018; 497(1): 39–45.
  37. Draman MS, Stechman M, Scott-Coombes D, et al. The Role of Thyrotropin Receptor Activation in Adipogenesis and Modulation of Fat Phenotype. Front Endocrinol (Lausanne). 2017; 8: 83.
  38. Liu T, Men Q, Su X, et al. Downregulated expression of TSHR is associated with distant metastasis in thyroid cancer. Oncol Lett. 2017; 14(6): 7506–7512.
  39. Schott M, Scherbaum WA. Autoimmune Thyroid Disease. Dtsch Arztebl. 2006; 103(45): A3023–A3032.
  40. Furmaniak J, Sanders J, Rees Smith B. Blocking type TSH receptor antibodies. Auto Immun Highlights. 2013; 4(1): 11–26.
  41. Ludwig RJ, Vanhoorelbeke K, Leypoldt F, et al. Mechanisms of Autoantibody-Induced Pathology. Front Immunol. 2017; 8: 603.
  42. Wall JR, Lahooti H. Pathogenesis of thyroid eye disease — does autoimmunity against the TSH receptor explain all cases? Endokrynol Pol. 2010; 61(2): 222–227.
  43. Iyer S, Bahn R. Immunopathogenesis of Graves' ophthalmopathy: the role of the TSH receptor. Best Pract Res Clin Endocrinol Metab. 2012; 26(3): 281–289.
  44. Weetman AP. Autoimmune thyroid disease: propagation and progression. Eur J Endocrinol. 2003; 148(1): 1–9.
  45. Janegova A, Janega P, Rychly B, et al. The role of Epstein-Barr virus infection in the development of autoimmune thyroid diseases. Endokrynol Pol. 2015; 66(2): 132–136.
  46. Cho BY. Clinical applications of TSH receptor antibodies in thyroid diseases. J Korean Med Sci. 2002; 17(3): 293–301.
  47. Oda Y, Sanders J, Roberts S, et al. Analysis of carbohydrate residues on recombinant human thyrotropin receptor. J Clin Endocrinol Metab. 1999; 84(6): 2119–2125.
  48. Nagayama Y, Namba H, Yokoyama N, et al. Role of asparagine-linked oligosaccharides in protein folding, membrane targeting, and thyrotropin and autoantibody binding of the human thyrotropin receptor. J Biol Chem. 1998; 273(50): 33423–33428.
  49. Siffroi-Fernandez S, Costagliola S, Paumel S, et al. Role of complex asparagine-linked oligosaccharides in the expression of a functional thyrotropin receptor. Biochem J. 2001; 354(Pt 2): 331–336.
  50. Frenzel R, Krohn K, Eszlinger M, et al. Sialylation of human thyrotropin receptor improves and prolongs its cell-surface expression. Mol Pharmacol. 2005; 68(4): 1106–1113.
  51. Nagayama Y, Nishihara E, Namba H, et al. Identification of the sites of asparagine-linked glycosylation on the human thyrotropin receptor and studies on their role in receptor function and expression. J Pharmacol Exp Ther. 2000; 295(1): 404–409.
  52. Russo D, Chazenbalk GD, Nagayama Y, et al. Site-directed mutagenesis of the human thyrotropin receptor: role of asparagine-linked oligosaccharides in the expression of a functional receptor. Mol Endocrinol. 1991; 5(1): 29–33.
  53. Huang GC, Collison KS, McGregor AM, et al. Expression of a human thyrotrophin receptor fragment in Escherichia coli and its interaction with the hormone and autoantibodies from patients with Graves' disease. J Mol Endocrinol. 1992; 8(2): 137–144.
  54. Misrahi M, Milgrom E. The TSH Receptor. In: Weetman AP, Grossman A. ed. Pharmacotherapeutics of the Thyroid Gland. Handbook of Experimental Pharmacology. Vol 128. Springer, Berlin 1997.
  55. Sanders J, Oda Y, Roberts SA, et al. Understanding the thyrotropin receptor function-structure relationship. Baillieres Clin Endocrinol Metab. 1997; 11(3): 451–479.
  56. Siffroi-Fernandez S, Giraud A, Lanet J, et al. Association of the thyrotropin receptor with calnexin, calreticulin and BiP. Efects on the maturation of the receptor. Eur J Biochem. 2002; 269(20): 4930–4937.
  57. McLachlan SM, Alpi K, Rapoport B. Review and hypothesis: does Graves' disease develop in non-human great apes? Thyroid. 2011; 21(12): 1359–1366.
  58. McLachlan SM, Rapoport B. Breaking tolerance to thyroid antigens: changing concepts in thyroid autoimmunity. Endocr Rev. 2014; 35(1): 59–105.
  59. Mikoś H, Mikoś M, Obara-Moszyńska M, et al. The role of the immune system and cytokines involved in the pathogenesis of autoimmune thyroid disease (AITD). Endokrynol Pol. 2014; 65(2): 150–155.
  60. Leteux C, Chai W, Loveless RW, et al. The cysteine-rich domain of the macrophage mannose receptor is a multispecific lectin that recognizes chondroitin sulfates A and B and sulfated oligosaccharides of blood group Lewis(a) and Lewis(x) types in addition to the sulfated N-glycans of lutropin. J Exp Med. 2000; 191(7): 1117–1126.
  61. Chazenbalk GD, Pichurin PN, Guo J, et al. Interactions between the mannose receptor and thyroid autoantigens. Clin Exp Immunol. 2005; 139(2): 216–224.
  62. Loke I, Kolarich D, Packer NH, et al. Emerging roles of protein mannosylation in inflammation and infection. Mol Aspects Med. 2016; 51: 31–55.
  63. Chen CR, Pichurin P, Nagayama Y, et al. The thyrotropin receptor autoantigen in Graves disease is the culprit as well as the victim. J Clin Invest. 2003; 111(12): 1897–1904.
  64. Seetharamaiah GS, Dallas JS, Patibandla SA, et al. Requirement of glycosylation of the human thyrotropin receptor ectodomain for its reactivity with autoantibodies in patients' sera. J Immunol. 1997; 158(6): 2798–2804.
  65. Goulabchand R, Vincent T, Batteux F, et al. Impact of autoantibody glycosylation in autoimmune diseases. Autoimmun Rev. 2014; 13(7): 742–750.
  66. Maverakis E, Kim K, Shimoda M, et al. Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review. J Autoimmun. 2015; 57: 1–13.
  67. Gińdzieńska-Sieśkiewicz E, Klimiuk PA, Domysławska I, et al. Zaburzenia glikozylacji immunoglobuliny G w przebiegu reumatoidalnego zapalenia stawów. Postepy Hig Med Dosw. 2005; 59: 485–489.
  68. Biermann MHC, Griffante G, Podolska MJ, et al. Sweet but dangerous — the role of immunoglobulin G glycosylation in autoimmunity and inflammation. Lupus. 2016; 25(8): 934–942.
  69. Franco JS, Amaya-Amaya J, Anaya JM. Thyroid disease and autoimmune diseases. In: Anaya JM, Shoenfeld Y, Rojas-Villarraga A, Levy RA, Cervera R. ed. Autoimmunity: From Bench to Bedside [Internet]. El Rosario University Press, Bogota 2013.
  70. Zhao L, Liu M, Gao Y, et al. Glycosylation of sera thyroglobulin antibody in patients with thyroid diseases. Eur J Endocrinol. 2013; 168(4): 585–592.
  71. Yuan S, Li Q, Zhang Y, et al. Changes in anti-thyroglobulin IgG glycosylation patterns in Hashimoto's thyroiditis patients. J Clin Endocrinol Metab. 2015; 100(2): 717–724.
  72. Martin T, Simurina M, Zabczynska M, et al. Decreased IgG core fucosylation, a player in antibody-dependent cell-mediated cytotoxicity, is associated with autoimmune thyroid diseases. Biorxiv. 2018.
  73. Rodrigues J, Balmaña M, Macedo J, et al. Glycosylation in cancer: Selected roles in tumour progression, immune modulation and metastasis. Cell Immunol. 2018; 333: 46–57.
  74. Szkudlinski MW, Fremont V, Ronin C, et al. Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships. Physiol Rev. 2002; 82(2): 473–502.
  75. Ząbczyńska M, Kozłowska K, Pocheć E. Glycosylation in the Thyroid Gland: Vital Aspects of Glycoprotein Function in Thyrocyte Physiology and Thyroid Disorders. Int J Mol Sci. 2018; 19(9).