{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T14:12:53Z","timestamp":1777990373917,"version":"3.51.4"},"posted":{"date-parts":[[2026,5,5]]},"group-title":"Immunology","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T00:00:00Z","timestamp":1777939200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institute of Diabetes and Digestive and Kidney Diseases"},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases","award":["DK134489"],"award-info":[{"award-number":["DK134489"]}]},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases","award":["DK082753"],"award-info":[{"award-number":["DK082753"]}]},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases","award":["DK078244"],"award-info":[{"award-number":["DK078244"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,5]]},"abstract":"<jats:p>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 to form immune complexes, some of which deposit in glomeruli. 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-\u03baB pathway, including RELA, the gene encoding the NF-\u03baB subunit p65. However, the mechanisms by which NF-\u03baB 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 that have constitutively activated NF-\u03baB, we report that inhibition of NF-\u03baB\/p65 by a selective IKK\u03b2 inhibitor TPCA-1 reduced phosphorylation of NF-\u03baB\/p65 at S536 and decreased production of IgA1 and, conversely, increased Gd-IgA1 production. This 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 the NF-\u03baB\/p65 with co-transcriptional factor SP1, a transcriptional activator of C1GALT1, suggesting that NF-\u03baB pathway affects IgA1 O-glycosylation via SP1 transcriptional control of C1GALT1 expression. Furthermore, prolonged I\u039a\u039a\u03b2 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 provide functional evidence for involvement of NF-\u03baB\/p65 and its transcriptional partners in IgA1 O-glycosylation.<\/jats:p>","DOI":"10.64898\/2026.04.30.721982","type":"posted-content","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T13:25:18Z","timestamp":1777987518000},"source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of p65 NF-\u03baB enhances production of galactose-deficient IgA1 through suppression of C1GALT1 and SP1 in plasmablast-like cell subpopulations"],"prefix":"10.64898","author":[{"given":"Taylor","family":"Person","sequence":"first","affiliation":[{"name":"University of Alabama at Birmingham"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maggie","family":"Phillips","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Terri","family":"Rice","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stacy","family":"Hall","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce A","family":"Julian","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dana V","family":"Rizk","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Novak","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4033-1360","authenticated-orcid":false,"given":"Colin","family":"Reily","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.04.30.721982","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T13:25:18Z","timestamp":1777987518000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.04.30.721982"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,5]]},"references-count":0,"URL":"https:\/\/doi.org\/10.64898\/2026.04.30.721982","relation":{},"subject":[],"published":{"date-parts":[[2026,5,5]]},"subtype":"preprint"}}