Nuclear Export of the NF-κB Inhibitor IκBα Is Required for Proper B Cell and Secondary Lymphoid Tissue Formation

SummaryThe 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