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IKKε and TBK1 are essential components of the IRF3 signaling pathway

Nature Immunology volume 4, pages 491–496 (2003)Cite this article

Abstract

The transcription factors interferon regulatory factor 3 (IRF3) and NF-κB are required for the expression of many genes involved in the innate immune response. Viral infection, or the binding of double-stranded RNA to Toll-like receptor 3, results in the coordinate activation of IRF3 and NF-κB. Activation of IRF3 requires signal-dependent phosphorylation, but little is known about the signaling pathway or kinases involved. Here we report that the noncanonical IκB kinase homologs, IκB kinase-ε (IKKε) and TANK-binding kinase-1 (TBK1), which were previously implicated in NF-κB activation, are also essential components of the IRF3 signaling pathway. Thus, IKKε and TBK1 have a pivotal role in coordinating the activation of IRF3 and NF-κB in the innate immune response.

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Figure 1: Both IKKε and TBK1 induce IFN-β and RANTES.
Figure 2: IKKε and TBK1 activate IRF3.
Figure 3: IKKε and TBK1 are required for viral activation of PRDIII-I.
Figure 4: IKKε and TBK1 are required for IRF3 activation by dsRNA.
Figure 5: TRIF activates IRF3.
Figure 6: IKKε and TBK1 are required for activation of IRF3 by TRIF.

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Acknowledgements

We thank C. Lin, W. Niu, N. Silverman, J. Rosains, I. Udalova, J. Tian, L-A. Feeney, K. Nagashima, M. Dorsch, B. Monks and B. Barnes for technical support and discussions. This work was supported by the Wellcome Trust (K.A.F.), the Cancer Research Institute (S.M.M.) and grants R01 GM54060 (K.A.F., D.T.G.) and R01 AI20642 (S.M.M., T.M.) from the US National Institutes of Health.

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Author notes

  1. Katherine A. Fitzgerald and Sarah M. McWhirter: These two authors contributed equally to this work.

Authors and Affiliations

  1. Division of Infectious Disease & Immunology, University of Massachusetts Medical School, Worcester, 01605, MA, USA

    Katherine A. Fitzgerald, Daniel C. Rowe, Eicke Latz & Douglas T. Golenbock

  2. Department of Molecular and Cellular Biology, Harvard University, Cambridge, 02138, MA, USA

    Sarah M. McWhirter & Tom Maniatis

  3. Department of Inflammation, Millennium Pharmaceuticals, Inc., Cambridge, 02139, MA, USA

    Kerrie L. Faia, Anthony J. Coyle & Sha-Mei Liao

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Correspondence to Sha-Mei Liao or Tom Maniatis.

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Competing interests

K.L.F., A.J.C. and S.-M.L. are employees of Millennium Pharmaceuticals, Inc. of Cambridge, Massachusetts, USA. K.A.F., S.M.M., D.C.R., E.L., D.T.G. and T.M. have no competing financial interests.

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Fitzgerald, K., McWhirter, S., Faia, K. et al. IKKε and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 4, 491–496 (2003). https://doi.org/10.1038/ni921

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