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DNA damage selectively induces post-translational modifications at lysine residues 277 and 309 of the human ubiquitin-binding protein NEMO to promote NF-\u03baB signaling, but the physiological importance of these modifications in vivo remains unclear. Here, we show that a newly developed mouse model (NEMO\n                    <jats:sup>DK<\/jats:sup>\n                    ) carrying germline arginine substitutions of the corresponding NEMO lysine residues exhibits B-cell-intrinsic defects in germinal center formation and anti-viral humoral responses. Mechanistically, we identify in NEMO\n                    <jats:sup>DK<\/jats:sup>\n                    B-cells a CD40-specific NF-\u03baB signaling defect that is not linked to the well-characterized canonical or noncanonical NF-\u03baB pathways. These B-cells fail to secure sustained NEMO monoubiquitination following CD40-induced ROS generation, which specifically reduces downstream RelA (p65) signaling required for the transcriptomic and epigenetic remodeling underlying homotypic B-cell aggregation, cell proliferation, class-switch recombination, and antibody-secreting cell generation. Our results establish a physiological role of murine NEMO K270 and K302 in linking CD40 engagement to B-cell responses through enabling sustained NEMO modification and RelA transcriptional activity.\n                  <\/jats:p>","DOI":"10.1038\/s44318-026-00875-0","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:17:08Z","timestamp":1785424628000},"page":"6229-6266","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["NF-\u03baB\/RelA signaling required for CD40-induced humoral immunity depends on specific NEMO lysine residues in mice"],"prefix":"10.1038","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1099-6799","authenticated-orcid":false,"given":"Donna","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelly 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