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

Fumiyo Ikeda, Christina Maria Hecker, Alexis Rozenknop, Rolf Dietrich Nordmeier, Vladimir Rogov, Kay Hofmann, Shizuo Akira, Volker Dötsch, Ivan Dikic

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

TANK-binding kinase 1 (TBK1/NAK/T2K) and I-κB Kinase (IKK-i/IKK-ε) 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-β or RANTES promoters. The importance of the ULD of TBK1 in LPS- or poly(I:C)-stimulated IFN-β 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.

Original languageEnglish
Pages (from-to)3451-3462
Number of pages12
JournalEMBO Journal
Volume26
Issue number14
DOIs
Publication statusPublished - Jul 25 2007
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Fingerprint Dive into the research topics of 'Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genes'. Together they form a unique fingerprint.

Cite this