The nuclear expression and action of the nuclear factor kappa B (NF-κB) transcription factor requires signal-coupled phosphorylation and degradation of the IκB inhibitors, which normally bind and sequester this pleiotropically active factor in the cytoplasm. The subsequent molecular events that regulate the termination of nuclear NF-κB action remain poorly defined, although the activation of de novo IκBα gene expression by NF-κB likely plays a key role. Our studies now demonstrate that the RelA subunit of NF-κB is subject to inducible acetylation and that acetylated forms of RelA interact weakly, if at all, with IκBα. Acetylated RelA is subsequently deacetylated through a specific interaction with histone deacetylase 3 (HDAC3). This deacetylation reaction promotes effective binding to IκBα and leads in turn to IκBα-dependent nuclear export of the complex through a chromosomal region maintenance-1 (CRM-1)-dependent pathway. Deacetylation of RelA by HDAC3 thus acts as an intranuclear molecular switch that both controls the duration of the NF-κB transcriptional response and contributes to the replenishment of the depleted cytoplasmic pool of latent NF-κB-IκBα complexes.
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