Defective Galactosylation and Clearance of IgA1 Molecules as a Possible Etiopathogenic Factor in IgA Nephropathy1

Městecký, Jiří; Tomana, Milan; Crowley-Nowick, Peggy A.; Moldoveanu, Zina; Julian, Bruce A.; Jackson, Susan

doi:10.1159/000422410

Cited by 202 publications

(133 citation statements)

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“…Already this enzyme has been used successfully to construct synthetic glycopeptides containing specifically placed O-glycans to allow exploration of the ligand binding specificity of human P-selectin (9,16). In addition, the availability of the core 1 ␤3-Gal-T and, as described in our accompanying manuscript (61), the gene encoding the enzyme will allow assessment of the postulated role of the core 1 ␤3-Gal-T in Tn syndrome and IgA nephropathy (1,21,(23)(24)(25)(26).…”

Section: Figmentioning

confidence: 99%

“…It has been proposed that exposure of the Tn antigen in erythrocytes (Tn syndrome) (1) and in the hinge region of IgA (IgA nephropathy) (21)(22)(23) results in immune recognition and attack by a naturally circulating anti-Tn. These diseases may be caused by deficiency of core 1 ␤3-Gal-T (24 -26), but the exact pathogenesis is unknown because the core 1 ␤3-Gal-T has not been purified, and the gene(s) encoding core 1 ␤3-Gal-T has not been cloned.…”

mentioning

confidence: 99%

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Purification, Characterization, and Subunit Structure of Rat Core 1 β1,3-Galactosyltransferase

Ju¹,

Cummings²,

Canfield³

2002

Journal of Biological Chemistry

107

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The O-linked oligosaccharides (O-glycans) in mammalian glycoproteins are classified according to their core structures. Among the most common is the core 1 disaccharide structure consisting of Gal␤133GalNAc␣13Ser/ Thr, which is also the precursor for many extended Oglycan structures. The key enzyme for biosynthesis of core 1 O-glycan from the precursor GalNAc-␣-Ser/Thr is UDP-Gal:GalNAc-␣-Ser/Thr ␤3-galactosyltransferase (core1 ␤3-Gal-T). Core 1 ␤3-Gal-T activity, which requires Mn 2؉ , was solubilized from rat liver membranes and purified 71,034-fold to apparent homogeneity (>90% purity) in 5.7% yield by ion exchange chromatography on SP-Sepharose, affinity chromatography on immobilized asialo-bovine submaxillary mucin, and gel filtration chromatography on Superose 12. The purified enzyme is free of contaminating glycosyltransferases. Two peaks of core 1 ␤3-Gal-T activity were identified in the final step on Superose 12. One peak of activity contained protein bands on non-reducing SDS-PAGE of ϳ84-and ϳ86-kDa disulfide-linked dimers, whereas the second peak of activity contained monomers of ϳ43 kDa. Reducing SDS-PAGE of these proteins gave ϳ42-and ϳ43-kDa monomers. Both the 84/86-kDa dimers and the 42/43-kDa monomers have the same novel N-terminal sequence. The purified enzyme, which is remarkably stable, has an apparent K m for UDP-Gal of 630 M and an apparent V max of 206 mol/mg/h protein using GalNAc␣1-O-phenyl as the acceptor. The reaction product was generated using asialo-bovine submaxillary mucin as an acceptor; treatment with O-glycosidase generated the expected disaccharide Gal␤133GalNAc. These studies demonstrate that activity of the core 1 ␤1,3-Gal-T from rat liver is contained within a single, novel, disulfide-bonded, dimeric enzyme.

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Section: Figmentioning

confidence: 99%

mentioning

confidence: 99%

Purification, Characterization, and Subunit Structure of Rat Core 1 β1,3-Galactosyltransferase

Ju¹,

Cummings²,

Canfield³

2002

Journal of Biological Chemistry

107

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“…It is estimated that over half of mammalian proteins are glycosylated. Patients with several autoimmune disorders, chronic inflammatory diseases, and some infectious diseases exhibit abnormal glycosylation of serum immunoglobulins and other glycoproteins (1)(2)(3)(4)(5). The biological functions of these modifications in health and disease have become a significant area of interest in biomedical research (6).…”

mentioning

confidence: 99%

“…Their altered expression and aberrant glycosylation have made them potential targets as biomarkers for early detection of cancer (7). Immunoglobulin A1 (IgA1) 1 contains both O-and N-glycans ( Fig. 1).…”

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confidence: 99%

Clustered O-Glycans of IgA1

Takahashi

Wall

Suzuki

et al. 2010

Molecular & Cellular Proteomics

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Glycosylation is one of the most common post-translational modifications of proteins. It is estimated that over half of mammalian proteins are glycosylated. Patients with several autoimmune disorders, chronic inflammatory diseases, and some infectious diseases exhibit abnormal glycosylation of serum immunoglobulins and other glycoproteins (1-5). The biological functions of these modifications in health and disease have become a significant area of interest in biomedical research (6). A subset of these glycoproteins has clustered sites of O-glycosylation with serine-and threonine-rich stretches within the amino acid sequence. Mucins, such as membrane-associated MUC1, are perhaps the best known family of proteins that are heavily O-glycosylated. Their altered expression and aberrant glycosylation have made them potential targets as biomarkers for early detection of cancer (7). Immunoglobulin A1 (IgA1) 1 contains both O-and N-glycans (Fig. 1). Aberrant O-glycosylation of IgA1 is involved in the pathogenesis of IgA nephropathy (IgAN) and the closely related Henoch-Schö nlein purpura nephritis (1, 8). Interestingly, the aberrantly glycosylated molecules, IgA1 in IgAN and MUC1 in cancer, are recognized by the immune system as neoepitopes as evidenced by formation of specific antibodies (9 -11). Mucin-like bacterial surface proteins exhibit similar properties: the molecules have clustered bacterial O-glycans that mediate cellular adhesion, and blocking antibodies target these glycan-containing epitopes (12).An O-glycosylated protein from a single source contains a population of variably O-glycosylated isoforms that show a distinct distribution of microheterogeneity of the O-glycan chains in terms of number, sites of attachment, and composition. Characterizing these clustered sites and understanding how the distributions change under different biological conditions or disease states are an analytical challenge. Enzymatic or chemical release of O-glycans is not selective. The heterogeneity, composition, and quantitative aspects of different O-glycan chains can be assessed and quantified by gas chromatographic and/or mass spectrometric techniques.

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“…Recent studies using different assays found differences in the hinge-region O-glycans that could have structural and functional implications relevant to the pathogenesis of IgA nephropathy. [26][27][28][29] This O-glycan aggregate is large compared with other proteins, and has anionic charge secondary sialization of sugars. Series of O-glycans tend to provide an extended structure on the protein domain of the IgA1 molecule.…”

Section: Disturbances In Iga Regulationmentioning

confidence: 99%

Pathogenesis of IgA nephropathy: A Review

Akash

2006

Dial. Transplant.

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Defective Galactosylation and Clearance of IgA1 Molecules as a Possible Etiopathogenic Factor in IgA Nephropathy1

Cited by 202 publications

References 0 publications

Purification, Characterization, and Subunit Structure of Rat Core 1 β1,3-Galactosyltransferase

Purification, Characterization, and Subunit Structure of Rat Core 1 β1,3-Galactosyltransferase

Clustered O-Glycans of IgA1

Pathogenesis of IgA nephropathy: A Review

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