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Histone H3 phosphorylation by IKK-α is critical for cytokine-induced gene expression

Abstract

Cytokine-induced activation of the IκB kinases (IKK) IKK-α and IKK-β is a key step involved in the activation of the NF-κB pathway1,2,3,4. Gene-disruption studies of the murine IKK genes have shown that IKK-β, but not IKK-α, is critical for cytokine-induced IκB degradation5,6,7. Nevertheless, mouse embryo fibroblasts deficient in IKK-α are defective in the induction of NF-κB-dependent transcription7,8,9. These observations raised the question of whether IKK-α might regulate a previously undescribed step to activate the NF-κB pathway that is independent of its previously described cytoplasmic role in the phosphorylation of IκBα. Here we show that IKK-α functions in the nucleus to activate the expression of NF-κB-responsive genes after stimulation with cytokines. IKK-α interacts with CREB-binding protein and in conjunction with Rel A is recruited to NF-κB-responsive promoters and mediates the cytokine-induced phosphorylation and subsequent acetylation of specific residues in histone H3. These results define a new nuclear role of IKK-α in modifying histone function that is critical for the activation of NF-κB-directed gene expression.

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Figure 1: Both IKK-α-/- and IKK-β-/- cells are defective in TNF-α-induced NF-κB activation.
Figure 2: TNF-α treatment leads to IKK-α association with the IκBα and IL-8 promoters.
Figure 3: IKK-α interacts with the CBP transactivation domain.
Figure 4: IKK-α promoter association is not strictly dependent on p65 binding and results in increased CBP transcriptional activity.
Figure 5: Requirement for IKK-α in histone H3 phosphorylation.

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Acknowledgements

We thank J. Guo for assistance, A. Herrera and M. Singh for preparation of the figures, J. Darrah for preparing the manuscript, and T. Collins for GAL4–CBP constructs.

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Correspondence to Richard B. Gaynor.

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The authors declare that they have no competing financial interests.

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Yamamoto, Y., Verma, U., Prajapati, S. et al. Histone H3 phosphorylation by IKK-α is critical for cytokine-induced gene expression. Nature 423, 655–659 (2003). https://doi.org/10.1038/nature01576

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