IKK-β inhibitor TPCA-1 increases Gd-IgA1 production and decreases C1GALT1 expression in EBV-immortalized B cells from human donors
- 1Department of Medicine, University of Alabama at Birmingham
- 2Department of Microbiology, University of Alabama at Birmingham
Abstract
IgA nephropathy (IgAN) is a common primary glomerulonephritis characterized by glomerular immune-complex deposits with (co)dominant IgA. These deposits are enriched for IgA1 glycoforms with some O- glycans deficient in galactose (Gd-IgA1). Circulating Gd-IgA1 is bound by IgG autoantibodies forming immune complexes, some of which deposit in glomeruli and induce kidney injury. Genomic and immunologic studies indicate involvement of pro-inflammatory signaling pathways in the production of Gd-IgA1 in IgAN. Genomic studies identified multiple genetic loci associated with IgAN and suggested a convergence on the NF-κB pathway, including RELA , the gene encoding the NF-κB subunit p65. However, the mechanisms by which NF-κB pathways may affect O -glycosylation in IgA1-producing cells are unknown. Using EBV-immortalized B cells derived from peripheral-blood mononuclear cells of IgAN patients and healthy controls, we report that inhibition of p65 NF-κB by an IKK-β inhibitor, TPCA-1, reduced phosphorylation of p65 NF-κB and decreased production of IgA1 and, conversely, increased Gd-IgA1 production. This effect on Gd-IgA1 was likely related to reduced expression of C1GALT1 gene that encodes the enzyme responsible for galactosylation of IgA1 O -glycans. Flow-cytometry imaging revealed changes in nuclear translocation and co-localization of p65 NF-κB with co-transcriptional factor SP1, a transcriptional activator of C1GALT1 , suggesting that NF-κB pathway and SP1 association affect IgA1 O -glycosylation through transcriptional control of C1GALT1 expression. Furthermore, prolonged IKK-β inhibition altered B-cell subpopulations, enhancing generation of cells with a plasmablast-like phenotype, characterized by high SSC MFI and CD138 expression. Together, these findings implicate p65 NF-κB and its transcriptional partners in IgA1 O -glycosylation.
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BibTeX
@article{person2026ikkβ,
title = {{IKK-β inhibitor TPCA-1 increases Gd-IgA1 production and decreases C1GALT1 expression in EBV-immortalized B cells from human donors}},
author = {Taylor Person and Maggie Phillips and Terri Rice and Stacy Hall and Bruce A. Julian and Dana V. Rizk and Jan Novak and Colin Reily},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1913226},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1913226/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - IKK-β inhibitor TPCA-1 increases Gd-IgA1 production and decreases C1GALT1 expression in EBV-immortalized B cells from human donors
AU - Taylor Person
AU - Maggie Phillips
AU - Terri Rice
AU - Stacy Hall
AU - Bruce A. Julian
AU - Dana V. Rizk
AU - Jan Novak
AU - Colin Reily
PY - 2026
DA - 2026/10/28
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1913226
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1913226/full
AB - IgA nephropathy (IgAN) is a common primary glomerulonephritis characterized by glomerular immune-complex deposits with (co)dominant IgA. These deposits are enriched for IgA1 glycoforms with some O- glycans deficient in galactose (Gd-IgA1). Circulating Gd-IgA1 is bound by IgG autoantibodies forming immune complexes, some of which deposit in glomeruli and induce kidney injury. Genomic and immunologic studies indicate involvement of pro-inflammatory signaling pathways in the production of Gd-IgA1 in IgAN. Genomic studies identified multiple genetic loci associated with IgAN and suggested a convergence on the NF-κB pathway, including RELA , the gene encoding the NF-κB subunit p65. However, the mechanisms by which NF-κB pathways may affect O -glycosylation in IgA1-producing cells are unknown. Using EBV-immortalized B cells derived from peripheral-blood mononuclear cells of IgAN patients and healthy controls, we report that inhibition of p65 NF-κB by an IKK-β inhibitor, TPCA-1, reduced phosphorylation of p65 NF-κB and decreased production of IgA1 and, conversely, increased Gd-IgA1 production. This effect on Gd-IgA1 was likely related to reduced expression of C1GALT1 gene that encodes the enzyme responsible for galactosylation of IgA1 O -glycans. Flow-cytometry imaging revealed changes in nuclear translocation and co-localization of p65 NF-κB with co-transcriptional factor SP1, a transcriptional activator of C1GALT1 , suggesting that NF-κB pathway and SP1 association affect IgA1 O -glycosylation through transcriptional control of C1GALT1 expression. Furthermore, prolonged IKK-β inhibition altered B-cell subpopulations, enhancing generation of cells with a plasmablast-like phenotype, characterized by high SSC MFI and CD138 expression. Together, these findings implicate p65 NF-κB and its transcriptional partners in IgA1 O -glycosylation.
SN - 1664-3224
ER -