Novel roles of TLR3 tyrosine phosphorylation and PI3 kinase in double-stranded RNA signaling

Nat Struct Mol Biol. 2004 Nov;11(11):1060-7. doi: 10.1038/nsmb847. Epub 2004 Oct 24.


Double-stranded RNA (dsRNA), a frequent byproduct of virus infection, is recognized by Toll-like receptor 3 (TLR3) to mediate innate immune response to virus infection. TLR3 signaling activates the transcription factor IRF-3 by its Ser/Thr phosphorylation, accompanied by its dimerization and nuclear translocation. It has been reported that the Ser/Thr kinase TBK-1 is essential for TLR3-mediated activation and phosphorylation of IRF-3. Here we report that dsRNA-activated phosphorylation of two specific tyrosine residues of TLR3 is essential for initiating two distinct signaling pathways. One involves activation of TBK-1 and the other recruits and activates PI3 kinase and the downstream kinase, Akt, leading to full phosphorylation and activation of IRF-3. When PI3 kinase is not recruited to TLR3 or its activity is blocked, IRF-3 is only partially phosphorylated and fails to bind the promoter of the target gene in dsRNA-treated cells. Thus, the PI3K-Akt pathway plays an essential role in TLR3-mediated gene induction.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus
  • Blotting, Western
  • Cell Line
  • Cell Nucleus / metabolism
  • Chromatin Immunoprecipitation
  • Dimerization
  • Electrophoresis, Gel, Two-Dimensional
  • Enzyme Activation
  • Humans
  • Immunoprecipitation
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / physiology*
  • Models, Biological
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositol 3-Kinases / physiology*
  • Phosphorylation
  • Plasmids / metabolism
  • Protein Structure, Tertiary
  • RNA, Double-Stranded / chemistry*
  • RNA, Small Interfering / chemistry
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / physiology*
  • Signal Transduction
  • Threonine / chemistry
  • Toll-Like Receptor 3
  • Toll-Like Receptors
  • Tyrosine / chemistry*


  • Membrane Glycoproteins
  • RNA, Double-Stranded
  • RNA, Small Interfering
  • Receptors, Cell Surface
  • TLR3 protein, human
  • Toll-Like Receptor 3
  • Toll-Like Receptors
  • Threonine
  • Tyrosine
  • Phosphatidylinositol 3-Kinases