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

Milada Stuchlova Horynova, Alena Vrablikova, Tyler J. Stewart, Kazuo Takahashi, Lydie Czernekova, Koshi Yamada, Hitoshi Suzuki, Bruce A. Julian, Matthew B. Renfrow, Jan Novak, Milan Raska

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Abstract

BackgroundGalactose-deficient O-glycans in the hinge region (HR) of immunoglobulin A1 (IgA1) play a key role in the pathogenesis of IgA nephropathy (IgAN). O-Glycans of circulatory IgA1 consist of N-acetylgalactosamine (GalNAc) with a β1,3-linked galactose; both sugars may be sialylated. In patients with IgAN, α2,6-sialylated GalNAc is a frequent form of the galactose-deficient O-glycans. Prior analyses of IgA1-producing cells had indicated that α2,6-sialyltransferase II (ST6GalNAc-II) is likely responsible for sialylation of GalNAc of galactose-deficient IgA1, but direct evidence is missing. MethodsWe produced a secreted variant of recombinant human ST6GalNAc-II and an IgA1 fragment comprised of Cα1-HR-Cα2. This IgA1 fragment and a synthetic HR peptide with enzymatically attached GalNAc residues served as acceptors. ST6GalNAc-II activity was assessed in vitro and the attachment of sialic acid to these acceptors was detected by lectin blot and mass spectrometry. ResultsST6GalNAc-II was active with both acceptors. High-resolution mass spectrometry analysis revealed that up to three sialic acid residues were added to the GalNAc residues of the HR glycopeptide. ConclusionsOur 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.

Original languageEnglish
Pages (from-to)234-238
Number of pages5
JournalNephrology Dialysis Transplantation
Volume30
Issue number2
DOIs
Publication statusPublished - 01-02-2015

All Science Journal Classification (ASJC) codes

  • Nephrology
  • Transplantation

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    Horynova, M. S., Vrablikova, A., Stewart, T. J., Takahashi, K., Czernekova, L., Yamada, K., Suzuki, H., Julian, B. A., Renfrow, M. B., Novak, J., & Raska, M. (2015). N-Acetylgalactosaminide α2,6-sialyltransferase II is a candidate enzyme for sialylation of galactose-deficient IgA1, the key autoantigen in IgA nephropathy. Nephrology Dialysis Transplantation, 30(2), 234-238. https://doi.org/10.1093/ndt/gfu308