N-Acetylgalactosaminide α2,6-sialyltransferase II is a candidate enzyme for sialylation of galactose-deficient IgA1, the key autoantigen in IgA nephropathy

Horynová, Milada; Vráblíková, Alena; Stewart, Tyler J; Takahashi, Kazuo; Czerneková, Lýdie; Yamada, Koshi; Suzuki, Hitoshi; Julian, Bruce A.; Renfrow, Matthew B.; Novák, Jan; Raška, Milan

doi:10.1093/ndt/gfu308

Cited by 24 publications

(19 citation statements)

References 33 publications

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“…O-glycans consist of N-acetylgalactosamine (GalNAc) linked with galactose (Gal; β1,3-linkage). The GalNAc-Gal disaccharide may be sialylated (linked with sialic acids) on GalNAc (α2,6-linkage), Gal (α2,3-linkage), or both [15,16,19].…”

Section: Structure Of Human Igamentioning

confidence: 99%

The Role of IgA in the Pathogenesis of IgA Nephropathy

Perše

Večerić-Haler

2019

IJMS

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Immunoglobulin A (IgA) is the most abundant antibody isotype produced in humans, predominantly present in the mucosal areas where its main functions are the neutralization of toxins, prevention of microbial invasion across the mucosal epithelial barrier, and simultaneous maintenance of a physiologically indispensable symbiotic relationship with commensal bacteria. The process of IgA biosynthesis, interaction with receptors, and clearance can be disrupted in certain pathologies, like IgA nephropathy, which is the most common form of glomerulonephritis worldwide. This review summarizes the latest findings in the complex characteristics of the molecular structure and biological functions of IgA antibodies, offering an in-depth overview of recent advances in the understanding of biochemical, immunologic, and genetic factors important in the pathogenesis of IgA nephropathy.

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Section: Structure Of Human Igamentioning

confidence: 99%

The Role of IgA in the Pathogenesis of IgA Nephropathy

Perše

Večerić-Haler

2019

IJMS

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“…In addition, glomerular IgA immunodeposits in patients with IgAN are enriched for Gd-IgA1 glycoforms [6,7], further supporting the role of abnormal IgA1 O-glycosylation in pathogenesis of IgAN [9,10,28,32]. Previous studies of the origin of Gd-IgA1 indicated abnormalities in the biosynthetic process in IgA1-producing cells, specifically the altered expression of genes encoding several key glycosyltransferases [12][13][14]. Recent GWAS findings showed an association of IgAN with SNPs for critical glycosyltransferase and chaperone genes, C1GALT1 and COSMC.…”

Section: Discussionmentioning

confidence: 84%

“…Enzyme activities of C1GALT1 and ST6GalNAc-II mirrored the expression of the corresponding genes. Follow-up studies indicated that some cytokines (e.g., interleukin [IL]-4 and IL-6) can alter the expression of C1GALT1, COSMC, and/or ST6GALNAC2 genes to further dysregulate activities of the encoded enzymes [12][13][14]. These findings together suggested that elevated production of Gd-IgA1 in patients with IgAN was due to an abnormal biosynthesis in IgA1-secreting cells rather than galactose removal/degradation.…”

Section: Introductionmentioning

confidence: 99%

Leukemia Inhibitory Factor Signaling Enhances Production of Galactose-Deficient IgA1 in IgA Nephropathy

et al. 2020

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Objectives: IgA nephropathy (IgAN) is thought to involve an autoimmune process wherein galactose-deficient IgA1 (Gd-IgA1), recognized as autoantigen by autoantibodies, forms pathogenic immune complexes. Mounting evidence has implicated abnormal activation of some protein-tyrosine kinases (PTKs) in IgAN. Furthermore, genome-wide association studies (GWAS) of IgAN provided insight into disease pathobiology and genetics. A GWAS locus on chromosome 22q12 contains genes encoding leukemia inhibitory factor (LIF) and oncostatin M, interleukin (IL)-6-related cytokines implicated in mucosal immunity and inflammation. We have previously shown that IL-6 mediates overproduction of Gd-IgA1 K.Y. and Z.H. are co-first authors. C.D.W. and J.N. are co-senior authors.

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“…GalNAc-T2 was the identified as the key enzyme initiating glycosylation of IgA1 [75]. GalNAc-T14 is another candidate GalNAc-T involved in IgA1 HR O -glycosylation [12, 76]. Attachment of GalNAc is followed by addition of Gal from UDP-Gal catalyzed by C1GalT1.…”

Section: Figmentioning

confidence: 99%

IgA nephropathy enigma

Městecký

Novák

Moldoveanu

et al. 2016

Clinical Immunology

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IgA nephropathy (IgAN) is the leading cause of primary glomerulonephritis in the world. The disease is characterized by the presence of immune complexes in the circulation and in mesangial deposits with ensuing glomerular injury. Although in humans there are two IgA subclasses, only IgA1 molecules are involved. The exclusivity of participation of IgA1 in IgAN prompted extensive structural and immunological studies of the unique hinge region (HR) of IgA1, which is absent in otherwise highly homologous IgA2. HR of IgA1 with altered O-glycans serves as an antigen recognized by autoantibodies specific for aberrant HR glycans leading to the generation of nephritogenic immune complexes. However, there are several unresolved questions concerning the phylogenetic origin of human IgA1 HR, the structural basis of its antigenicity, the origin of antibodies specific for HR with altered glycan moieties, the regulatory defects in IgA1 glycosylation pathways, and the potential approaches applicable to the disease-specific interventions in the formation of nephritogenic immune complexes. This review focuses on the gaps in our knowledge of molecular and cellular events that are involved in the immunopathogenesis of IgAN.

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N-Acetylgalactosaminide α2,6-sialyltransferase II is a candidate enzyme for sialylation of galactose-deficient IgA1, the key autoantigen in IgA nephropathy

Abstract: Our data provide direct evidence that ST6GalNAc-II can sialylate GalNAc of galactose-deficient IgA1. As serum levels of galactose-deficient IgA1 with sialylated glycoforms are increased in IgAN patients, our data explain the corresponding part of the biosynthetic pathway.

Cited by 24 publications

References 33 publications

The Role of IgA in the Pathogenesis of IgA Nephropathy

The Role of IgA in the Pathogenesis of IgA Nephropathy

Leukemia Inhibitory Factor Signaling Enhances Production of Galactose-Deficient IgA1 in IgA Nephropathy

IgA nephropathy enigma

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