NF-κB/RelA signaling required for CD40-induced humoral immunity depends on specific NEMO lysine residues in mice

Abstract Oxidative stress and genotoxic damage activate NF-κB signaling through intracellular pathways distinct from those initiated by membrane receptors. DNA damage selectively induces post-translational modifications at lysine residues 277 and 309 of the human ubiquitin-binding protein NEMO to promote NF-κB signaling, but the physiological importance of these modifications in vivo remains unclear. Here, we show that a newly developed mouse model (NEMO DK ) 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 DK B-cells a CD40-specific NF-κB signaling defect that is not linked to the well-characterized canonical or noncanonical NF-κB 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.

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Publication Details

Journal
The EMBO Journal
Published
2026-07-30
DOI
https://doi.org/10.1038/s44318-026-00875-0
Primary Topic
NF-κB Signaling Pathways
Type
article
Field-Weighted Citation Impact
0.00

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article

NF-κB/RelA signaling required for CD40-induced humoral immunity depends on specific NEMO lysine residues in mice

Barry P. Sleckman, Shigeki Miyamoto, Dominique N. Lisiero, Donna Li et al.
The EMBO Journal
NF-κB Signaling Pathways
article

NF-κB/RelA signaling required for CD40-induced humoral immunity depends on specific NEMO lysine residues in mice

Barry P. Sleckman, Shigeki Miyamoto, Dominique N. Lisiero, Donna Li, Funita Phan, P. Khatri, Melba Marie Tejera, Alexander Hoffmann, Shelly M. Wuerzberger‐Davis, Cynthia C. Aguilar, Huy Q. Dinh, Jeffrey J. Bednarski, Aussie Suzuki, Yu-Chia Chen, Demin Wang, Irene Ong, Marulasiddappa Suresh, Thomas Cleven, Natalie Medina, Ning Wang, Mei Yu, Yuhong Chen, Avtar Roopra, Philippos Tsourkas
article en

Abstract

Abstract Oxidative stress and genotoxic damage activate NF-κB signaling through intracellular pathways distinct from those initiated by membrane receptors. DNA damage selectively induces post-translational modifications at lysine residues 277 and 309 of the human ubiquitin-binding protein NEMO to promote NF-κB signaling, but the physiological importance of these modifications in vivo remains unclear. Here, we show that a newly developed mouse model (NEMO DK ) 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 DK B-cells a CD40-specific NF-κB signaling defect that is not linked to the well-characterized canonical or noncanonical NF-κB 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.

The EMBO Journal
QB3 (US), University of Wisconsin System (US), University of Wisconsin–Madison (US), University of California, Los Angeles (US), Washington University in St. Louis (US), Wisconsin Institutes for Discovery (US), University of Alabama at Birmingham (US), University of Wisconsin Carbone Cancer Center (US), Versiti Blood Center of Wisconsin (US)
University of Wisconsin Carbone Cancer Center, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases
Openalex Percentile: Top 12%
NF-κB Signaling Pathways
DOIOpen Access PDFOpenAlex
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