Nuclear Export of the NF-[kappa]B Inhibitor I[kappa]B[alpha] Is Required for Proper B Cell and Secondary Lymphoid Tissue Formation

• Published in: Immunity (Cambridge, Mass.) Vol. 34; no. 2; p. 188
• Main Authors: Wuerzberger-Davis, Shelly M, Chen, Yuhong, Yang, David T, Kearns, Jeffrey D, Bates, Paul W, Lynch, Candace, Ladell, Nicholas C, Yu, Mei, Podd, Andrew, Zeng, Hu, Huang, Tony T, Wen, Renren, Hoffmann, Alexander, Wang, Demin, Miyamoto, Shigeki
• Format: Journal Article
• Language: English
• Published: Cambridge Elsevier Limited 25-02-2011
• Subjects: Immune system; Kinases; Migration; Mutation; Phosphorylation; Proteins; Rodents; Studies; Baltimore Maryland
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2011.01.014

The N-terminal nuclear export sequence (NES) of inhibitor of nuclear factor kappa B (NF-κB) alpha (IκBα) promotes NF-κB export from the cell nucleus to the cytoplasm, but the physiological role of this export regulation remains unknown. Here we report the derivation and analysis of genetically targeted mice harboring a germline mutation in IκBα NES. Mature B cells in the mutant mice displayed nuclear accumulation of inactive IκBα complexes containing a NF-κB family member, cRel, causing their spatial separation from the cytoplasmic IκB kinase. This resulted in severe reductions in constitutive and canonical NF-κB activities, synthesis of p100 and RelB NF-κB members, noncanonical NF-κB activity, NF-κB target gene induction, and proliferation and survival responses in B cells. Consequently, mice displayed defective B cell maturation, antibody production, and formation of secondary lymphoid organs and tissues. Thus, IκBα nuclear export is essential to maintain constitutive, canonical, and noncanonical NF-κB activation potentials in mature B cells in vivo.