A novel mutation in the Nfkb2 gene generates an NF-κB2 "super repressor"

Elena Tucker, Kristy O'Donnell, Martina Fuchsberger, Adrienne A. Hilton, Donald Metcalf, Kylie Greig, Natalie A. Sims, Julian M. Quinn, Warren S. Alexander, Douglas J. Hilton, Benjamin T. Kile, David M. Tarlinton, Robyn Starr

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66 Citations (Scopus)


The noncanonical NF-κB pathway regulates the development and function of multiple organs and cell lineages. We have generated mice harboring a novel mutation in Nfkb2 that prevents the processing of the inhibitory precursor, p100, into the active subunit, p52. Mutant mice express a complex phenotype with abnormalities in a variety of tissues, and with a spectrum that is more severe than in mice carrying a targeted deletion of Nfkb2. Signaling through the noncanonical pathway is ablated due to the absence of p52, resulting in disorganized splenic architecture and disrupted B cell development. The inhibitory precursor form of NF-κB2 interacts with RelA, preventing activation of RelA dimers in response to both canonical and noncanonical stimuli, which in combination with p52 deficiency, results in defective lymph node formation and bone homeostasis. These findings demonstrate a key role for NF-κB2 in the regulation of RelA activation and suggest overlap in the function of NF-κB members in canonical and noncanonical pathway signaling.

Original languageEnglish
Pages (from-to)7514-7522
Number of pages9
JournalJournal of Immunology
Issue number11
Publication statusPublished - 1 Dec 2007
Externally publishedYes

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