An N-terminal nuclear export signal is required for the nucleocytoplasmic shuttling of IκBα

Connie Johnson, Daniel Van Antwerp, Thomas J. Hope*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

206 Scopus citations


The potent transcriptional activities of Rel/NF-κB proteins are regulated in the cytoplasm and nucleus by the inhibitor, IκBα. The mechanism, by which IκBα can either sequester NF-κB in the cytoplasm or act as a nuclear post-induction repressor of NF-κB, is uncertain. We find that IκBα shuttles continuously between the nucleus and cytoplasm. This shuttling requires a previously unidentified CRM1-dependent nuclear export signal (NES) located within the N-terminal domain of IκBα at amino acids 45-55. Deletion or mutation of the N-terminal NES results in nuclear localization of IκBα. NF-κB (p65) association with IκBα affects steady-state localization but does not inhibit its shuttling. Endogenous complexes of IκBα-NF-κB shuttle and will accumulate in the nucleus when CRM1 export is blocked. We find TNFα can activate the nuclear IκBα-NF-κB complexes by the classical mechanism of proteasome-mediated degradation of IκBα. These studies reveal a more dynamic nucleocytoplasmic distribution for IκBα and NF-κB suggesting previously unknown strategies for regulating this ubiquitous family of transcription activators.

Original languageEnglish (US)
Pages (from-to)6682-6693
Number of pages12
JournalEMBO Journal
Issue number23
StatePublished - Dec 1 1999


  • IκBα-NF-κ
  • Nuclear export
  • Nucleocytoplasmic shuttling
  • Rel A

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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