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

The N-terminal nuclear export sequence (NES) of inhibitor of nuclear factor kappa B (NF-kappa B) alpha (I kappa B alpha) promotes NF-kappa B 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 I kappa B alpha NES. Mature B cells in the mutant mice displayed nuclear accumulation of inactive I kappa B alpha complexes containing a NF-kappa B family member, cReI, causing their spatial separation from the cytoplasmic I kappa B kinase. This resulted in severe reductions in constitutive and canonical NF-kappa B activities, synthesis of p100 and ReIB NF-kappa B members, noncanonical NF-kappa B activity, NF-kappa B 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, I kappa B alpha nuclear export is essential to maintain constitutive, canonical, and noncanonical NF-kappa B activation potentials in mature B cells in vivo.