Cytoplasmic IκBα Increases NF-κB-independent Transcription through Binding to Histone Deacetylase (HDAC) 1 and HDAC3

Abstract IκBα is an inhibitory molecule that sequesters NF-κB dimers in the cytoplasm of unstimulated cells. Upon stimulation, NF-κB moves to the nucleus and induces the expression of a variety of genes including IκBα. This newly synthesized IκBα also translocates to the nucleus, removes activated NF-κB from its target genes, and brings it back to the cytoplasm to terminate the phase of NF-κB activation. We show here that IκBα enhances the transactivation potential of several homeodomain-containing proteins such as HOXB7 and Pit-1 through a NF-κB-independent association with histone deacetylase (HDAC) 1 and HDAC3 but not with HDAC2, -4, -5, and -6. IκBα bound both HDAC proteins through its ankyrin repeats, and this interaction was disrupted by p65. Immunofluorescence experiments demonstrated further that IκBα acts by partially redirecting HDAC3 to the cytoplasm. At the same time, an IκBα mutant, which lacked a functional nuclear localization sequence, interacted very efficiently with HDAC1 and -3 and intensively enhanced the transactivation potential of Pit-1. Our results support the hypothesis that the NF-κB inhibitor IκBα regulates the transcriptional activity of homeodomain-containing proteins positively through cytoplasmic sequestration of HDAC1 and HDAC3, a mechanism that would assign a new and unexpected role to IκBα.