Abstract
Core 1 UDP-Gal: N-acetylgalactosaminyl-α1-O-Ser/Thr β3galactosyltransferase (core 1 β3galactosyltransferase, core 1 β3GalT, C1GALT1, T-synthase, EC 2.4.1.122) transfers the Gal from UDP-Gal to N-acetylgalactosaminyl-α1-O-Ser/Thr (Tn antigen) in a protein to form Galβ1,3GalNAc-α-Ser/Thr, the core 1 structure also known as T antigen (Fig. 15.1) in the mucin-type O-glycosylation pathway. This core 1 structure is the most common precursor for a variety of complex structures of mucin-type O-glycans (O-glycans) usually found in many mucins, membrane glycoproteins, and secreted glycoproteins (Ju et al. 2011a). These O-glycans include mono- and di-sialyl core 1, sialyl Lewis x (SLeX) core 2 O-glycans with or without poly-N-acetyllactosamine structures, and extended core 1 O-glycans with sulfation such as sulfo-sialyl Lewis x (MECA79 epitope). The O-glycans on glycoproteins play important roles in immunity (Ellies et al. 1998; Homeister et al. 2001; Yeh et al. 2001), cell–cell interactions (selectins and their ligands) (Homeister et al. 2001; Leppanen et al. 1999; McEver et al. 1995; Wilkins et al. 1996; Yeh et al. 2001), vascular biology (Tenno et al. 2007), angiogenesis (Xia et al. 2004), lymphangiogenesis (Fu et al. 2008), and biogenesis and function of platelets (Wang et al. 2012). Biochemically and biologically, T-synthase is the key glycosyltransferase in the biosynthesis and biology of mucin-type O-glycan.
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Alexander WS, Viney EM, Zhang JG, Metcalf D, Kauppi M, Hyland CD, Carpinelli MR, Stevenson W, Croker BA, Hilton AA, Ellis S, Selan C, Nandurkar HH, Goodnow CC, Kile BT, Nicola NA, Roberts AW, Hilton DJ (2006) Thrombocytopenia and kidney disease in mice with a mutation in the C1galt1 gene. Proc Natl Acad Sci USA 103:16442–16447
Allen AC, Topham PS, Harper SJ, Feehally J (1997) Leucocyte beta 1,3 galactosyltransferase activity in IgA nephropathy. Nephrol Dial Transplant 12:701–706
Aryal RP, Ju T, Cummings RD (2010) The endoplasmic reticulum chaperone Cosmc directly promotes in vitro folding of T-synthase. J Biol Chem 285:2456–2462
Aryal RP, Ju T, Cummings RD (2012) Tight complex formation between Cosmc chaperone and its specific client non-native T-synthase leads to enzyme activity and client-driven dissociation. J Biol Chem 287:15317–15329
Beerman I, Novak J, Wyatt RJ, Julian BA, Gharavi AG (2007) The genetics of IgA nephropathy. Nat Clin Pract Nephrol 3:325–338
Berger EG (1999) Tn-syndrome. Biochim Biophys Acta 1455:255–268
Berger J, Hinglais N (1968) Intercapillary deposits of IgA-IgG. J Urol Nephrol (Paris) 74:694–695
Brockhausen I, Moller G, Pollex-Kruger A, Rutz V, Paulsen H, Matta KL (1992a) Control of O-glycan synthesis: specificity and inhibition of O-glycan core 1 UDP-galactose:N-acetylgalactosamine-alpha-R beta 3-galactosyltransferase from rat liver. Biochem Cell Biol = Biochim Biol Cell 70:99–108
Brockhausen I, Moller G, Pollex-Kruger A, Rutz V, Paulsen H, Matta KL (1992b) Control of O-glycan synthesis: specificity and inhibition of O-glycan core 1 UDP-galactose:N-acetylgalactosamine-alpha-R beta 3-galactosyltransferase from rat liver. Biochem Cell Biol 70:99–108
Crew VK, Singleton BK, Green C, Parsons SF, Daniels G, Anstee DJ (2008) New mutations in C1GALT1C1 in individuals with Tn positive phenotype. Br J Haematol 142:657–667
D’Amico G (2000) Natural history of idiopathic IgA nephropathy: role of clinical and histological prognostic factors. Am J Kidney Dis 36:227–237
Desai PR (2000) Immunoreactive T and Tn antigens in malignancy: role in carcinoma diagnosis, prognosis, and immunotherapy. Transfus Med Rev 14:312–325
Ellies LG, Tsuboi S, Petryniak B, Lowe JB, Fukuda M, Marth JD (1998) Core 2 oligosaccharide biosynthesis distinguishes between selectin ligands essential for leukocyte homing and inflammation. Immunity 9:881–890
Friedenreich V (1930) The Thomsen hemagglutination phenomenon, vol 1, Levin and Munskgaard, Copenhagen
Fu J, Gerhardt H, McDaniel JM, Xia B, Liu X, Ivanciu L, Ny A, Hermans K, Silasi-Mansat R, McGee S, Nye E, Ju T, Ramirez MI, Carmeliet P, Cummings RD, Lupu F, Xia L (2008) Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice. J Clin Invest 118:3725–3737
Fu J, Wei B, Wen T, Johansson ME, Liu X, Bradford E, Thomsson KA, McGee S, Mansour L, Tong M, McDaniel JM, Sferra TJ, Turner JR, Chen H, Hansson GC, Braun J, Xia L (2011) Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice. J Clin Invest 121:1657–1666
Furukawa K, Roth S (1985) Co-purification of galactosyltransferases from chick-embryo liver. Biochem J 227:573–582
Giannakakis K, Feriozzi S, Perez M, Faraggiana T, Muda AO (2007) Aberrantly glycosylated IgA1 in glomerular immune deposits of IgA nephropathy. J Am Soc Nephrol 18:3139–3146
Gouyer V, Leteurtre E, Zanetta JP, Lesuffleur T, Delannoy P, Huet G (2001) Inhibition of the glycosylation and alteration in the intracellular trafficking of mucins and other glycoproteins by GalNAcalpha-O-bn in mucosal cell lines: an effect mediated through the intracellular synthesis of complex GalNAcalpha-O-bn oligosaccharides. Front Biosci: J Virtual Libr 6:D1235–D1244
Hiki Y (2009) O-linked oligosaccharides of the IgA1 hinge region: roles of its aberrant structure in the occurrence and/or progression of IgA nephropathy. Clin Exp Nephrol 13:415–423
Homeister JW, Thall AD, Petryniak B, Maly P, Rogers CE, Smith PL, Kelly RJ, Gersten KM, Askari SW, Cheng G, Smithson G, Marks RM, Misra AK, Hindsgaul O, von Andrian UH, Lowe JB (2001) The alpha (1,3) fucosyltransferases FucT-IV and FucT-VII exert collaborative control over selectin-dependent leukocyte recruitment and lymphocyte homing. Immunity 15:115–126
Huang J, Byrd JC, Yoon WH, Kim YS (1992) Effect of benzyl-alpha-GalNAc, an inhibitor of mucin glycosylation, on cancer-associated antigens in human colon cancer cells. Oncol Res 4:507–515
Inoue M, Ton SM, Ogawa H, Tanizawa O (1991) Expression of Tn and sialyl-Tn antigens in tumor tissues of the ovary. Am J Clin Pathol 96:711–716
Inoue S, Sano H, Ohta M (2000) Growth suppression of Escherichia coli by induction of expression of mammalian genes with transmembrane or ATPase domains. Biochem Biophys Res Commun 268:553–561
Inoue T, Sugiyama H, Hiki Y, Takiue K, Morinaga H, Kitagawa M, Maeshima Y, Fukushima K, Nishizaki K, Akagi H, Narimatsu Y, Narimatsu H, Makino H (2010) Differential expression of glycogenes in tonsillar B lymphocytes in association with proteinuria and renal dysfunction in IgA nephropathy. Clin Immunol 136:447–455
Itzkowitz S (1992) Carbohydrate changes in colon carcinoma. APMIS Suppl 27:173–180
Itzkowitz S, Kjeldsen T, Friera A, Hakomori S, Yang US, Kim YS (1991) Expression of Tn, sialosyl Tn, and T antigens in human pancreas. Gastroenterology 100:1691–1700
Ju T, Cummings RD (2002) A unique molecular chaperone Cosmc required for activity of the mammalian core 1 beta 3-galactosyltransferase. Proc Natl Acad Sci USA 99:16613–16618
Ju T, Cummings RD (2005) Protein glycosylation: chaperone mutation in Tn syndrome. Nature 437:1252
Ju T, Cummings RD (2010) Functional assays for the molecular chaperone cosmc. Methods Enzymol 479:107–122
Ju T, Cummings RD, Canfield WM (2002a) Purification, characterization, and subunit structure of rat core 1 Beta1,3-galactosyltransferase. J Biol Chem 277:169–177
Ju T, Brewer K, D’Souza A, Cummings RD, Canfield WM (2002b) Cloning and expression of human core 1 beta1,3-galactosyltransferase. J Biol Chem 277:178–186
Ju T, Zheng Q, Cummings RD (2006) Identification of core 1 O-glycan T-synthase from caenorhabditis elegans. Glycobiology 16:947–958
Ju T, Aryal RP, Stowell CJ, Cummings RD (2008a) Regulation of protein O-glycosylation by the endoplasmic reticulum-localized molecular chaperone Cosmc. J Cell Biol 182:531–542
Ju T, Lanneau GS, Gautam T, Wang Y, Xia B, Stowell SR, Willard MT, Wang W, Xia JY, Zuna RE, Laszik Z, Benbrook DM, Hanigan MH, Cummings RD (2008b) Human tumor antigens Tn and sialyl Tn arise from mutations in Cosmc. Cancer Res 68:1636–1646
Ju T, Otto VI, Cummings RD (2011a) The Tn antigen-structural simplicity and biological complexity. Angewandte Chemie 50:1770–1791
Ju T, Xia B, Aryal RP, Wang W, Wang Y, Ding X, Mi R, He M, Cummings RD (2011b) A novel fluorescent assay for T-synthase activity. Glycobiology 21:352–362
Julian BA, Novak J (2004) IgA nephropathy: an update. Curr Opin Nephrol Hypertens 13:171–179
Klenk E, Uhlenbruck G (1960) On the isolation of mucoids containing neuraminic acid from human erythrocyte stroma, a contribution to the chemistry of agglutinogens. Hoppe Seylers Z Physiol Chem 319:151–160
Kudo T, Iwai T, Kubota T, Iwasaki H, Takayma Y, Hiruma T, Inaba N, Zhang Y, Gotoh M, Togayachi A, Narimatsu H (2002) Molecular cloning and characterization of a novel UDP-Gal: GalNAc (alpha) peptide beta 1,3-galactosyltransferase (C1Gal-T2), an enzyme synthesizing a core 1 structure of O-glycan. J Biol Chem 277:47724–47731
Kudo T, Iwai T, Kubota T, Iwasaki H, Takayma Y, Hiruma T, Inaba N, Zhang Y, Gotoh M, Togayachi A, Narimatsu H (2006) Molecular cloning and characterization of a novel UDP-Gal: GalNAcα peptide β1,3-galactosyltransferase (C1Gal-T2), an enzyme synthesizing a core 1 structure of O-glycan. J Biol Chem 277:47724–47731. J Biol Chem, 281:24999
Leppanen A, Mehta P, Ouyang YB, Ju T, Helin J, Moore KL, van Die I, Canfield WM, McEver RP, Cummings RD (1999) A novel glycosulfopeptide binds to P-selectin and inhibits leukocyte adhesion to P-selectin. J Biol Chem 274:24838–24848
Levy M, Berger J (1988) Worldwide perspective of IgA nephropathy. Am J Kidney Dis 12:340–347
Li GS, Zhang H, Lv JC, Shen Y, Wang HY (2007) Variants of C1GALT1 gene are associated with the genetic susceptibility to IgA nephropathy. Kidney Int 71:448–453
Lin YR, Reddy BV, Irvine KD (2008) Requirement for a core 1 galactosyltransferase in the Drosophila nervous system. Dev Dyn 237:3703–3714
Lundstrom M, Jeansson S, Olofsson S (1987) Host cell-induced differences in the O-glycosylation of herpes simplex virus gC-1. II. Demonstration of cell-specific galactosyltransferase essential for formation of O-linked oligosaccharides. Virology 161:395–402
Malycha F, Eggermann T, Hristov M, Schena FP, Mertens PR, Zerres K, Floege J, Eitner F (2009) No evidence for a role of cosmc-chaperone mutations in European IgA nephropathy patients. Nephrol Dial Transplant 24:321–324
Mattu TS, Pleass RJ, Willis AC, Kilian M, Wormald MR, Lellouch AC, Rudd PM, Woof JM, Dwek RA (1998) The glycosylation and structure of human serum IgA1, Fab, and Fc regions and the role of N-glycosylation on Fc alpha receptor interactions. J Biol Chem 273:2260–2272
McEver RP, Moore KL, Cummings RD (1995) Leukocyte trafficking mediated by selectin-carbohydrate interactions. J Biol Chem 270:11025–11028
Mendicino J, Sivakami S, Davila M, Chandrasekaran EV (1982) Purification and properties of UDP-gal: N-acetylgalactosaminide mucin: beta 1,3-galactosyltransferase from swine trachea mucosa. J Biol Chem 257:3987–3994
Mestecky J, Tomana M, Moldoveanu Z, Julian BA, Suzuki H, Matousovic K, Renfrow MB, Novak L, Wyatt RJ, Novak J (2008) Role of aberrant glycosylation of IgA1 molecules in the pathogenesis of IgA nephropathy. Kidney Blood Press Res 31:29–37
Mestecky J, Raska M, Julian BA, Gharavi AG, Renfrow MB, Moldoveanu Z, Novak L, Matousovic K, Novak J (2013) IgA nephropathy: molecular mechanisms of the disease. Annu Rev Pathol 24:217–240
Mi R, Song L, Wang Y, Ding X, Zeng J, Lehoux S, Aryal RP, Wang J, Crew VK, van Die I, Chapman AB, Cummings RD, Ju T (2012) Epigenetic silencing of Cosmc in human leukocytes expressing Tn antigen. J Biol Chem 287:41523–41533
Moreau R, Dausset J, Bernard J, Moullec J (1957) Acquired hemolytic anemia with polyagglutinability of erythrocytes by a new factor present in normal blood. Bull Mem Soc Med Hop Paris 73:569–587
Muller R, Hulsmeier AJ, Altmann F, Ten Hagen K, Tiemeyer M, Hennet T (2005) Characterization of mucin-type core-1 beta1-3 galactosyltransferase homologous enzymes in Drosophila melanogaster. FEBS J 272:4295–4305
Novak J, Julian BA, Tomana M, Mestecky J (2008) IgA glycosylation and IgA immune complexes in the pathogenesis of IgA nephropathy. Semin Nephrol 28:78–87
Palaima E, Leymarie N, Stroud D, Mizanur RM, Hodgkin J, Gravato-Nobre MJ, Costello CE, Cipollo JF (2010) The Caenorhabditis elegans bus-2 mutant reveals a new class of O-glycans affecting bacterial resistance. J Biol Chem 285:17662–17672
Piller V, Piller F, Fukuda M (1990) Biosynthesis of truncated O-glycans in the T cell line Jurkat. Localization of O-glycan initiation. J Biol Chem 265:9264–9271
Pirulli D, Crovella S, Ulivi S, Zadro C, Bertok S, Rendine S, Scolari F, Foramitti M, Ravani P, Roccatello D, Savoldi S, Cerullo G, Lanzilotta SG, Bisceglia L, Zelante L, Floege J, Alexopoulos E, Kirmizis D, Ghiggeri GM, Frasca G, Schena FP, Amoroso A (2009) Genetic variant of C1GalT1 contributes to the susceptibility to IgA nephropathy. J Nephrol 22:152–159
Prokop O, Uhlenbruck G (1969) N-acetyl-d-galactosamine in tumor cell membranes: demonstration by means of Helix agglutinins. Med Welt 46:2515–2519
Qin W, Zhou Q, Yang LC, Li Z, Su BH, Luo H, Fan JM (2005) Peripheral B lymphocyte beta 1,3-galactosyltransferase and chaperone expression in immunoglobulin A nephropathy. J Int Med 258:467–477
Qin W, Zhong X, Fan JM, Zhang YJ, Liu XR, Ma XY (2008) External suppression causes the low expression of the Cosmc gene in IgA nephropathy. Nephrol Dial Transplant 23:1608–1614
Schachter H, McGuire EJ, Roseman S (1971) Sialic acids. 13. A uridine diphosphate d-galactose: mucin galactosyltransferase from porcine submaxillary gland. J Biol Chem 246:5321–5328
Schietinger A, Philip M, Yoshida BA, Azadi P, Liu H, Meredith SC, Schreiber H (2006) A mutant chaperone converts a wild-type protein into a tumor-specific antigen. Science 314:304–308
Schjoldager KT, Vakhrushev SY, Kong Y, Steentoft C, Nudelman AS, Pedersen NB, Wandall HH, Mandel U, Bennett EP, Levery SB, Clausen H (2012) Probing isoform-specific functions of polypeptide GalNAc-transferases using zinc finger nuclease glycoengineered SimpleCells. Proc Natl Acad Sci USA 109:9893–9898
Springer GF (1984) T and Tn, general carcinoma autoantigens. Science 224:1198–1206
Springer GF (1997) Immunoreactive T and Tn epitopes in cancer diagnosis, prognosis, and immunotherapy. J Mol Med 75:594–602
Steentoft C, Vakhrushev SY, Vester-Christensen MB, Schjoldager KT, Kong Y, Bennett EP, Mandel U, Wandall H, Levery SB, Clausen H (2011) Mining the O-glycoproteome using zinc-finger nuclease-glycoengineered simple cell lines. Nat Methods 8:977–982
Stojanovic D, Vischer P, Hughes RC (1984) Glycosyl transferases of baby hamster kidney cells and ricin-resistant mutants. O-glycan biosynthesis. Eur J Biochem 138:551–562
Sun Q, Ju T, Cummings RD (2011) The transmembrane domain of the molecular chaperone Cosmc directs its localization to the endoplasmic reticulum. J Biol Chem 286:11529–11542
Suzuki H, Moldoveanu Z, Hall S, Brown R, Vu HL, Novak L, Julian BA, Tomana M, Wyatt RJ, Edberg JC, Alarcon GS, Kimberly RP, Tomino Y, Mestecky J, Novak J (2008) IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1. J Clin Invest 118:629–639
Tenno M, Ohtsubo K, Hagen FK, Ditto D, Zarbock A, Schaerli P, von Andrian UH, Ley K, Le D, Tabak LA, Marth JD (2007) Initiation of protein O glycosylation by the polypeptide GalNAcT-1 in vascular biology and humoral immunity. Mol Cell Biol 27:8783–8796
Terasawa K, Furumoto H, Kamada M, Aono T (1996) Expression of Tn and sialyl-Tn antigens in the neoplastic transformation of uterine cervical epithelial cells. Cancer Res 56:2229–2232
Thomsen O (1927) Ein vermehrungsfahiges Agens als Veranderer des isoagglutinatorischen Verhaltens der roten Blutkorperchen, eine bisher unbekannte Quelle der Fehlbestimmung. Z Immunitatsforsch Exp Ther 52:85–107
Thurnher M, Clausen H, Fierz W, Lanzavecchia A, Berger EG (1992) T cell clones with normal or defective O-galactosylation from a patient with permanent mixed-field polyagglutinability. Eur J Immunol 22:1835–1842
Tsuchiya A, Kanno M, Kawaguchi T, Endo Y, Zhang GJ, Ohtake T, Kimijima II (1999) Prognostic relevance of Tn expression in breast cancer. Breast Cancer 6:175–180
Tsuji T, Osawa T (1986) Carbohydrate structures of bovine submaxillary mucin. Carbohydr Res 151:391–402
Wang Y, Ju T, Ding X, Xia B, Wang W, Xia L, He M, Cummings RD (2010) Cosmc is an essential chaperone for correct protein O-glycosylation. Proc Natl Acad Sci USA 107:9228–9233
Wang Y, Jobe SM, Ding X, Choo H, Archer DR, Mi R, Ju T, Cummings RD (2012) Platelet biogenesis and functions require correct protein O-glycosylation. Proc Natl Acad Sci USA 109:16143–16148
Wilkins PP, McEver RP, Cummings RD (1996) Structures of the O-glycans on P-selectin glycoprotein ligand-1 from HL-60 cells. J Biol Chem 271:18732–18742
Xia L, Ju T, Westmuckett A, An G, Ivanciu L, McDaniel JM, Lupu F, Cummings RD, McEver RP (2004) Defective angiogenesis and fatal embryonic hemorrhage in mice lacking core 1-derived O-glycans. J Cell Biol 164:451–459
Xie LS, Qin W, Fan JM, Huang J, Xie XS, Li Z (2010) The role of C1GALT1C1 in lipopolysaccharide-induced IgA1 aberrant O-glycosylation in IgA nephropathy. Clin Invest Med 33:E5–E13
Yamada K, Kobayashi N, Ikeda T, Suzuki Y, Tsuge T, Horikoshi S, Emancipator SN, Tomino Y (2010) Down-regulation of core 1 beta1,3-galactosyltransferase and Cosmc by Th2 cytokine alters O-glycosylation of IgA1. Nephrol Dial Transplant 25:3890–3897
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 105:957–969
Yoshida H, Fuwa TJ, Arima M, Hamamoto H, Sasaki N, Ichimiya T, Osawa K, Ueda R, Nishihara S (2008) Identification of the Drosophila core 1 beta1,3-galactosyltransferase gene that synthesizes T antigen in the embryonic central nervous system and hemocytes. Glycobiology 18:1094–1104
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Ju, T., Cummings, R.D. (2014). Core 1 β3Galactosyltransferase (C1GalT1, T-Synthase) and Its Specific Molecular Chaperone Cosmc (C1GalT1C1). In: Taniguchi, N., Honke, K., Fukuda, M., Narimatsu, H., Yamaguchi, Y., Angata, T. (eds) Handbook of Glycosyltransferases and Related Genes. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54240-7_65
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