SMRT derepression by the IkappaB kinase alpha: a prerequisite to NF-kappaB transcription and survival.
Understanding how signaling cascades stimulate chromatin-remodeling events through derepression is one of the foremost questions in the transcription field. Here, we demonstrate that NF-kappaB transcription requires IKKalpha to phosphorylate SMRT on chromatin, stimulating the exchange of corepressor for coactivator complexes. IKKalpha-induced phosphorylation coincides with a loss of chromatin-associated SMRT and HDAC3 and with nuclear export of the SMRT corepressor, events required for expression of the NF-kappaB-regulated cIAP-2 and IL-8 genes. Although SMRT derepression corresponds with the recruitment of TBL1/TBLR1, this complex alone is insufficient to relieve repression. Using a nonphosphorylatable SMRT protein, we demonstrate that IKKalpha-induced phosphorylation is required to recruit 14-3-3epsilon and Ubc5 for SMRT derepression. Failure of IKKalpha to stimulate the removal of SMRT from chromatin inhibits the recruitment of NF-kappaB to promoters, blocking transcription and sensitizing cells to apoptosis. Our work provides evidence that IKKalpha orchestrates SMRT derepression, a prerequisite for NF-kappaB transcription and survival.
Hoberg
Jamie E
JE
Department of Biochemistry and Molecular Genetics, The University of Virginia, Charlottesville, VA 22908, USA.
Yeung
Fan
F
Mayo
Marty W
MW
D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase; D007797:Laminin / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D056985:Nuclear Receptor Co-Repressor 2; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*
D002843:Chromatin; D004268:DNA-Binding Proteins; D007797:Laminin; C539130:NCOR2 protein, human; D016328:NF-kappa B; D056985:Nuclear Receptor Co-Repressor 2; D012097:Repressor Proteins; D012694:Serine; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human