title: Nuclear export of the NF-κB inhibitor IκBα is required for proper B cell and secondary lymphoid tissue formation.
abstract: 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.
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, 6159 Wisconsin Institute for Medical Research, 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Shelly M
authors.initials: SM
authors.lastname: Wuerzberger-Davis
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Chen
authors.forename: David T
authors.initials: DT
authors.lastname: Yang
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Kearns
authors.forename: Paul W
authors.initials: PW
authors.lastname: Bates
authors.forename: Candace
authors.initials: C
authors.lastname: Lynch
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Ladell
authors.forename: Mei
authors.initials: M
authors.lastname: Yu
authors.forename: Andrew
authors.initials: A
authors.lastname: Podd
authors.forename: Hu
authors.initials: H
authors.lastname: Zeng
authors.forename: Tony T
authors.initials: TT
authors.lastname: Huang
authors.forename: Renren
authors.initials: R
authors.lastname: Wen
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
authors.forename: Demin
authors.initials: D
authors.lastname: Wang
authors.forename: Shigeki
authors.initials: S
authors.lastname: Miyamoto
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death; D002455:Cell Division; D005786:Gene Expression Regulation / Q000235:genetics; D018095:Germ-Line Mutation; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000473:pathology; D008221:Lymphoid Tissue / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D049790:Nuclear Export Signals / Q000235:genetics / Q000502:physiology*; D009929:Organ Size; D010581:Peyer's Patches / Q000473:pathology; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D013154:Spleen / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D049790:Nuclear Export Signals; D020569:Proto-Oncogene Proteins c-rel; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase