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

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.
Mesh Terms:
Active Transport, Cell Nucleus, Blotting, Western, Cell Line, Cell Nucleus, Chromatin Immunoprecipitation, Dimerization, Electrophoresis, Gel, Two-Dimensional, Enzyme Activation, Humans, Immunoprecipitation, Membrane Glycoproteins, Models, Biological, Phosphatidylinositol 3-Kinases, Phosphorylation, Plasmids, Protein Structure, Tertiary, RNA, Double-Stranded, RNA, Small Interfering, Receptors, Cell Surface, Signal Transduction, Threonine, Toll-Like Receptor 3, Toll-Like Receptors, Tyrosine
Nat. Struct. Mol. Biol.
Date: Nov. 01, 2004
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