The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection

J Exp Med. 2004 Jun 21;199(12):1641-50. doi: 10.1084/jem.20040520.


Viral infection and stimulation with lipopolysaccharide (LPS) or double stranded RNA (dsRNA) induce phosphorylation of interferon (IFN) regulatory factor (IRF)-3 and its translocation to the nucleus, thereby leading to the IFN-beta gene induction. Recently, two IkappaB kinase (IKK)-related kinases, inducible IkappaB kinase (IKK-i) and TANK-binding kinase 1 (TBK1), were suggested to act as IRF-3 kinases and be involved in IFN-beta production in Toll-like receptor (TLR) signaling and viral infection. In this work, we investigated the physiological roles of these kinases by gene targeting. TBK1-deficient embryonic fibroblasts (EFs) showed dramatic decrease in induction of IFN-beta and IFN-inducible genes in response to LPS or dsRNA as well as after viral infection. However, dsRNA-induced expression of these genes was residually detected in TBK1-deficient cells and intact in IKK-i-deficient cells, but completely abolished in IKK-i/TBK1 doubly deficient cells. IRF-3 activation, in response not only to dsRNA but also to viral infection, was impaired in TBK1-deficient cells. Together, these results demonstrate that TBK1 as well as, albeit to a lesser extent, IKK-i play a crucial role in the induction of IFN-beta and IFN-inducible genes in both TLR-stimulated and virus-infected EFs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Nucleus / physiology
  • DNA-Binding Proteins / metabolism
  • Embryo, Mammalian
  • Fibroblasts / physiology
  • I-kappa B Kinase
  • Interferon Regulatory Factor-3
  • Lipopolysaccharides / pharmacology*
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / physiology*
  • Protein Transport
  • RNA, Double-Stranded / genetics*
  • Salmonella / immunology
  • Signal Transduction / genetics*
  • Transcription Factors / metabolism
  • Virus Diseases / physiopathology*


  • DNA-Binding Proteins
  • Interferon Regulatory Factor-3
  • Irf3 protein, mouse
  • Lipopolysaccharides
  • RNA, Double-Stranded
  • Transcription Factors
  • Tbk1 protein, mouse
  • Protein Serine-Threonine Kinases
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Ikbke protein, mouse