Cytoplasmic IkappaBalpha increases NF-kappaB-independent transcription through binding to histone deacetylase (HDAC) 1 and HDAC3.
IkappaBalpha is an inhibitory molecule that sequesters NF-kappaB dimers in the cytoplasm of unstimulated cells. Upon stimulation, NF-kappaB moves to the nucleus and induces the expression of a variety of genes including IkappaBalpha. This newly synthesized IkappaBalpha also translocates to the nucleus, removes activated NF-kappaB from its target genes, and brings it back to the cytoplasm to terminate the phase of NF-kappaB activation. We show here that IkappaBalpha enhances the transactivation potential of several homeodomain-containing proteins such as HOXB7 and Pit-1 through a NF-kappaB-independent association with histone deacetylase (HDAC) 1 and HDAC3 but not with HDAC2, -4, -5, and -6. IkappaBalpha bound both HDAC proteins through its ankyrin repeats, and this interaction was disrupted by p65. Immunofluorescence experiments demonstrated further that IkappaBalpha acts by partially redirecting HDAC3 to the cytoplasm. At the same time, an IkappaBalpha 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-kappaB inhibitor IkappaBalpha 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 IkappaBalpha.
Viatour
Patrick
P
Laboratory of Medical Chemistry and Human Genetics, Center for Cellular and Molecular Therapy, University of Liège, Sart-Tillman, 4000 Liège, Belgium.
Legrand-Poels
Sylvie
S
van Lint
Carine
C
Warnier
Michael
M
Merville
Marie-Paule
MP
Gielen
Jacques
J
Piette
Jacques
J
Bours
Vincent
V
Chariot
Alain
A
D017089:Ankyrin Repeat / Q000502:physiology; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D011485:Protein Binding; D021381:Protein Transport; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000502:physiology; D015533:Transcriptional Activation; D000099186:Histone Deacetylase 3
D004268:DNA-Binding Proteins; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; D000099186:Histone Deacetylase 3; C000606204:NFKBIA protein, human; C494187:POU1F1 protein, human; C110550:HDAC1 protein, human