Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. Baldwin, A. S. The NF-κB and IκB proteins: new discoveries and insights. Annu. Rev. Immunol. 14, 649–681 (1996)

    Article  CAS  PubMed  Google Scholar 

  2. Ghosh, S., May, M. J. & Kopp, E. B. NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu. Rev. Immunol. 16, 225–260 (1998)

    Article  CAS  PubMed  Google Scholar 

  3. Silverman, N. & Maniatis, T. NF-κB signaling pathways in mammalian and insect innate immunity. Genes Dev. 15, 2321–2342 (2001)

    Article  CAS  PubMed  Google Scholar 

  4. Zandi, E. & Karin, M. Bridging the gap: composition, regulation, and physiological function of the IκB kinase complex. Mol. Cell. Biol. 19, 4547–4551 (1999)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Takeda, K. et al. Limb and skin abnormalities in mice lacking IKKα. Science 284, 313–316 (1999)

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Hu, Y. et al. Abnormal morphogenesis but intact IKK activation in mice lacking the IKKα subunit of IκB kinase. Science 284, 316–320 (1999)

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Li, Q. et al. IKK1-deficient mice exhibit abnormal development of skin and skeleton. Genes Dev. 13, 1322–1328 (1999)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sizemore, N., Lerner, N., Dombrowski, N., Sakurai, H. & Stark, G. R. Distinct roles of the IκB kinase α and β subunits in liberating nuclear factor κB (NF-κB) from IκB and in phosphorylating the p65 subunit of NF-κB. J. Biol. Chem. 277, 3863–3869 (2002)

    Article  CAS  PubMed  Google Scholar 

  9. Li, X. et al. IKKα, IKKβ and NEMO/IKKγ are each required for the NF-κB mediated inflammatory response program. J. Biol. Chem. 277, 45129–45140 (2002)

    Article  CAS  PubMed  Google Scholar 

  10. Birbach, A. et al. Signaling molecules of the NF-κB pathway shuttle constitutively between cytoplasm and nucleus. J. Biol. Chem. 277, 10842–10851 (2002)

    Article  CAS  PubMed  Google Scholar 

  11. Janknecht, R. & Hunter, T. Transcription. A growing coactivator network. Nature 383, 22–23 (1996)

    Article  ADS  CAS  PubMed  Google Scholar 

  12. Goodman, R. H. & Smolik, S. CBP/p300 in cell growth, transformation, and development. Genes Dev. 14, 1553–1577 (2000)

    CAS  PubMed  Google Scholar 

  13. Zhong, H., Voll, R. E. & Ghosh, S. Phosphorylation of NF-κB p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300. Mol. Cell 1, 661–671 (1998)

    Article  CAS  PubMed  Google Scholar 

  14. Zhong, H., May, M. J., Jimi, E. & Ghosh, S. The phosphorylation status of nuclear NF-κB determines its association with CBP/p300 or HDAC-1. Mol. Cell 9, 625–636 (2002)

    Article  CAS  PubMed  Google Scholar 

  15. Sakurai, H., Chiba, H., Miyoshi, H., Sugita, T. & Toriumi, W. IκB kinases phosphorylate NF-κB p65 subunit on serine 536 in the transactivation domain. J. Biol. Chem. 274, 30353–30356 (1999)

    Article  CAS  PubMed  Google Scholar 

  16. Madrid, L. V., Mayo, M. W., Reuther, J. Y. & Baldwin, A. S. Jr Akt stimulates the transactivation potential of the RelA/p65 subunit of NF-κB through utilization of the IκB kinase and activation of the mitogen-activated protein kinase p38. J. Biol. Chem. 276, 18934–18940 (2001)

    Article  CAS  PubMed  Google Scholar 

  17. Gerritsen, M. E. et al. CREB-binding protein/p300 are transcriptional coactivators of p65. Proc. Natl Acad. Sci. USA 94, 2927–2932 (1997)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang, C. Y., Mayo, M. W. & Baldwin, A. S. J. TNFα- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-κB. Science 274, 784–787 (1996)

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Van Antwerp, D. J., Martin, S. J., Kafri, T., Green, D. R. & Verma, I. M. Suppression of TNF-α-induced apoptosis by NF-κB. Science 274, 787–789 (1996)

    Article  ADS  CAS  PubMed  Google Scholar 

  20. Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000)

    Article  ADS  CAS  PubMed  Google Scholar 

  21. Cheung, P., Allis, C. D. & Sassone-Corsi, P. Signaling to chromatin through histone modifications. Cell 103, 263–271 (2000)

    Article  CAS  PubMed  Google Scholar 

  22. Cheung, P. et al. Synergistic coupling of histone H3 phosphorylation and acetylation in response to epidermal growth factor stimulation. Mol. Cell 5, 905–915 (2000)

    Article  CAS  PubMed  Google Scholar 

  23. Lo, W.-S. et al. Phosphorylation of serine 10 in histone H3 is functionally linked in vitro and in vivo to Gcn5-mediated acetylation at lysine 14. Mol. Cell 5, 917–926 (2000)

    Article  CAS  PubMed  Google Scholar 

  24. Sassone-Corsi, P. et al. Requirement of Rsk-2 for epidermal growth factor-activated phosphorylation of histone H3. Science 285, 886–891 (1999)

    Article  CAS  PubMed  Google Scholar 

  25. Thomson, S. et al. The nucleosomal response associated with immediate-early gene induction is mediated via alternative MAP kinase cascades: MSK1 as a potential histone H3/HMG-14 kinase. EMBO J. 18, 4779–4793 (1999)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Saccani, S., Pantano, S. & Natoli, G. p38-dependent marking of inflammatory genes for increased NF-κB recruitment. Nature Immunol. 3, 69–75 (2002)

    Article  CAS  Google Scholar 

  27. Anest, V. et al. A nucleosomal function for IκB kinase-α in NF-κB-dependent gene expression. Nature 423, 659–663 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  28. Senftleben, U. et al. Activation by IKKα of a second, evolutionary conserved, NF-κB signaling pathway. Science 293, 1495–1499 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  29. Yamamoto, Y. et al. IKKγ/NEMO facilitates the recruitment of the IκB proteins into the IκB kinase complex. J. Biol. Chem. 276, 36327–36336 (2001)

    Article  CAS  PubMed  Google Scholar 

Download references


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.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Richard B. Gaynor.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing