title: Cytokines alter IgA1 O-glycosylation by dysregulating C1GalT1 and ST6GalNAc-II enzymes.
abstract: IgA nephropathy (IgAN), the most common primary glomerulonephritis, is characterized by renal immunodeposits containing IgA1 with galactose-deficient O-glycans (Gd-IgA1). These immunodeposits originate from circulating immune complexes consisting of anti-glycan antibodies bound to Gd-IgA1. As clinical disease onset and activity of IgAN often coincide with mucosal infections and dysregulation of cytokines, we hypothesized that cytokines may affect IgA1 O-glycosylation. We used IgA1-secreting cells derived from the circulation of IgAN patients and healthy controls and assessed whether IgA1 O-glycosylation is altered by cytokines. Of the eight cytokines tested, only IL-6 and, to a lesser degree, IL-4 significantly increased galactose deficiency of IgA1; changes in IgA1 O-glycosylation were robust for the cells from IgAN patients. These cytokines reduced galactosylation of the O-glycan substrate directly via decreased expression of the galactosyltransferase C1GalT1 and, indirectly, via increased expression of the sialyltransferase ST6GalNAc-II, which prevents galactosylation by C1GalT1. These findings were confirmed by siRNA knockdown of the corresponding genes and by in vitro enzyme reactions. In summary, IL-6 and IL-4 accentuated galactose deficiency of IgA1 via coordinated modulation of key glycosyltransferases. These data provide a mechanism explaining increased immune-complex formation and disease exacerbation during mucosal infections in IgAN patients.
authors.affiliation: From the University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Milan
authors.initials: M
authors.lastname: Raska
authors.forename: Koshi
authors.initials: K
authors.lastname: Yamada
authors.forename: Zina
authors.initials: Z
authors.lastname: Moldoveanu
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Julian
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wyatt
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tomino
authors.forename: Ali G
authors.initials: AG
authors.lastname: Gharavi
authors.forename: Jan
authors.initials: J
authors.lastname: Novak
mesh_terms: D000328:Adult; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology*; D005260:Female; D005690:Galactose / Q000172:deficiency / Q000378:metabolism; D005700:Galactosyltransferases / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D005922:Glomerulonephritis, IGA / Q000201:enzymology / Q000473:pathology; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism*; D015847:Interleukin-4 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008297:Male; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D011134:Polysaccharides / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012799:Sialyltransferases / Q000378:metabolism*
chemical_list: D016207:Cytokines; D007070:Immunoglobulin A; D015850:Interleukin-6; D011134:Polysaccharides; D034741:RNA, Small Interfering; D015847:Interleukin-4; C505293:C1GALT1 protein, human; D005700:Galactosyltransferases; D012799:Sialyltransferases; C088391:galactosyl-1-3-N-acetylgalactosaminyl-specific 2,6-sialyltransferase; D019158:N-Acetylneuraminic Acid; D005690:Galactose
keywords: Glycosylation; IgA Nephropathy; IgA1; Immunology; Kidney; Mucosal Immunology; Nephrology; O-Glycans