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

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.

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Figure 1: TNF-α-induced nuclear accumulation of endogenous IKK-α.
Figure 2: Promoter-associated IKK-α is essential for TNF-α-induced NF-κB-dependent gene expression and histone H3 phosphorylation.
Figure 3: IKK-α directly phosphorylates histone H3 in vitro.
Figure 4: IKK-α modulates global levels of histone H3 phosphorylation.

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Acknowledgements

We thank D. Kashatus for critical reading of the manuscript. We appreciate scientific discussions with Y. Yamamoto and R. Gaynor. Support was provided by the NIH and by the UNC breast cancer SPORE program to A.S.B., and by the UNC Comprehensive Center for Inflammatory Disorders.

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Correspondence to Albert S. Baldwin.

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Anest, V., Hanson, J., Cogswell, P. et al. A nucleosomal function for IκB kinase-α in NF-κB-dependent gene expression. Nature 423, 659–663 (2003). https://doi.org/10.1038/nature01648

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