A nucleosomal function for IκB kinase-α in NF-κB-dependent gene expression

Vasiliki Anest, Julie L. Hanson, Patricia C. Cogswell, Kris A. Steinbrecher, Brian D. Strahl and Albert S. Baldwin ()
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Vasiliki Anest: Lineberger Comprehensive Cancer Center
Julie L. Hanson: Lineberger Comprehensive Cancer Center
Patricia C. Cogswell: Lineberger Comprehensive Cancer Center
Kris A. Steinbrecher: Lineberger Comprehensive Cancer Center
Brian D. Strahl: Lineberger Comprehensive Cancer Center
Albert S. Baldwin: Lineberger Comprehensive Cancer Center

Nature, 2003, vol. 423, issue 6940, 659-663

Abstract: Abstract NF-κB is a principal transcriptional regulator of diverse cytokine-mediated processes and is tightly controlled by the IκB kinase complex (IKK-α/β/γ). IKK-β and IKK-γ are critical for cytokine-induced NF-κB function, whereas IKK-α is thought to be involved in other regulatory pathways1,2,3,4. However, recent data suggest a role for IKK-α in NF-κB-dependent gene expression in response to cytokine treatment1,5,6,7. Here we demonstrate nuclear accumulation of IKK-α after cytokine exposure, suggesting a nuclear function for this protein. Consistent with this, chromatin immunoprecipitation (ChIP) assays reveal that IKK-α was recruited to the promoter regions of NF-κB-regulated genes on stimulation with tumour-necrosis factor-α. Notably, NF-κB-regulated gene expression is suppressed by the loss of IKK-α and this correlates with a complete loss of gene-specific phosphorylation of histone H3 on serine 10, a modification previously associated with positive gene expression. Furthermore, we show that IKK-α can directly phosphorylate histone H3 in vitro, suggesting a new substrate for this kinase. We propose that IKK-α is an essential regulator of NF-κB-dependent gene expression through control of promoter-associated histone phosphorylation after cytokine exposure. These findings provide additional insight into the role of the IKK complex in NF-κB-regulated gene expression.

Date: 2003
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DOI: 10.1038/nature01648

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