View the Current Issue

Article

  • The EMBO Journal (2007) 26, 3451 - 3462
  • doi:10.1038/sj.emboj.7601773

Published online: 28 June 2007

Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genes

Fumiyo Ikeda1,2, Christina Maria Hecker1, Alexis Rozenknop1,3, Rolf Dietrich Nordmeier1, Vladimir Rogov3,4, Kay Hofmann5, Shizuo Akira6,7, Volker Dötsch3 and Ivan Dikic1,2

  1. Institute of Biochemistry II, Goethe University Medical School, Frankfurt, Germany
  2. Tumor Biology Program, Mediterranean Institute for Life Sciences, Split, Croatia
  3. Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany
  4. Institute of Protein Research, Puschino, Russia
  5. Bioinformatics Group, Miltenyi Biotec GmbH, Köln, Germany
  6. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
  7. ERATO, Japan Science and Technology Agency, Osaka, Japan

Correspondence to:

Ivan Dikic, Institute of Biochemistry II, Frankfurt, Johann Wolfgang Goethe-Universität, Goethe University Medical School, Theodor-Stern-Kai 7, Frankfurt 60590, Germany. Tel.: +49 69 6301 83647; Fax: +49 69 6301 5577; E-mail: Ivan.Dikic@biochem2.de

Received 23 January 2007; Accepted 30 May 2007

TANK-binding kinase 1 (TBK1/NAK/T2K) and I-kappaB Kinase (IKK-i/IKK-alt epsilon) play important roles in the regulation of interferon (IFN)-inducible genes during the immune response to bacterial and viral infections. Cell stimulation with ssRNA virus, dsDNA virus or gram-negative bacteria leads to activation of TBK1 or IKK-i, which in turn phosphorylates the transcription factors, IFN-regulatory factor (IRF) 3 and IRF7, promoting their translocation in the nucleus. To understand the molecular basis of activation of TBK1, we analyzed the sequence of TBK1 and IKK-i and identified a ubiquitin-like domain (ULD) adjacent to their kinase domains. Deletion or mutations of the ULD in TBK1 or IKK-i impaired activation of respective kinases, failed to induce IRF3 phosphorylation and nuclear localization and to activate IFN-beta or RANTES promoters. The importance of the ULD of TBK1 in LPS- or poly(I:C)-stimulated IFN-beta production was demonstrated by reconstitution experiments in TBK1-IKK-i-deficient cells. We propose that the ULD is a regulatory component of the TBK1/IKK-i kinases involved in the control of the kinase activation, substrate presentation and downstream signaling pathways.

  • Keywords:

    • innate immunity signal,
    • interferon-inducible gene,
    • TANK-binding kinase 1,
    • ubiquitin,
    • ubiquitin-like domain