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An N‐terminal nuclear export signal is required for the nucleocytoplasmic shuttling of IκBα
Author(s) -
Johnson Connie,
Van Antwerp Daniel,
Hope Thomas J.
Publication year - 1999
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/18.23.6682
Subject(s) - nuclear export signal , biology , cytoplasm , nuclear transport , nuclear localization sequence , microbiology and biotechnology , cell nucleus , nucleus , importin
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.