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Molecular and Cellular Biology, January 2006, p. 457-471, Vol. 26, No. 2
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.2.457-471.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

I{kappa}B Kinase {alpha}-Mediated Derepression of SMRT Potentiates Acetylation of RelA/p65 by p300

Jamie E. Hoberg,1 Anita E. Popko,1,2 Catherine S. Ramsey,1 and Marty W. Mayo1*

Department of Biochemistry and Molecular Genetics, The University of Virginia, Charlottesville, Virginia 22908,1 Institute of Technical Biochemistry, Technical University of Lodz, 90-924 Lodz, Poland2

Received 15 September 2005/ Accepted 8 October 2005

Over the last several years, significant progress has been made in identifying chromatin-regulated events that govern NF-{kappa}B transcription. Using either laminin attachment or tumor necrosis factor alpha as a physiological stimulus of NF-{kappa}B activation, we demonstrate that I{kappa}B kinase {alpha} (IKK{alpha}) is recruited to chromatin in distinct phases. In the initial phase, IKK{alpha} is responsible for derepressing the silencing mediator for retinoic acid and thyroid hormone receptor (SMRT)-histone deacetylase 3 (HDAC3) corepressor complex from the p50 homodimer. However, in the latter phase, chromatin-bound IKK{alpha} coordinates the simultaneous phosphorylation of RelA/p65(S536) and SMRT(S2410) as detected by chromatin immunoprecipitation (ChIP) assays. Although phosphorylated SMRT remains bound to the active p50-RelA/p65 heterodimer of NF-{kappa}B, derepression of SMRT is evidenced by the loss of chromatin-associated HDAC3 activity. ChIP and re-ChIP analysis demonstrates that phosphorylation of RelA/p65(S536) and SMRT(S2410) occurs prior to acetylation of RelA/p65 at K310. Moreover, IKK{alpha}-induced phosphorylation of RelA/p65(S536) displaces corepressor activity, allowing p300-mediated acetylation of RelA/p65. Introduction of nonphosphorylatable mutants of RelA/p65 and SMRT proteins or the inhibition of IKK activity results in active repression of NF-{kappa}B promoters by tethering the SMRT-HDAC3 complex. Similar to phosphorylation within the Rel homology domain of RelA/p65, which governs an exchange of HDAC1 for CBP/p300 acetyltransferases, we demonstrate that phosphorylation within the transactivation domain of RelA/p65(S536) displaces SMRT-HDAC3 repressor activity, allowing p300 to acetylate RelA/p65.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Genetics, Box 800733, University of Virginia, Charlottesville, VA 22908. Phone: (434) 924-2509. Fax: (434) 982-1026. E-mail: mwm3y{at}virginia.edu.

Molecular and Cellular Biology, January 2006, p. 457-471, Vol. 26, No. 2
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.2.457-471.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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