Nature Structural & Molecular Biology11, 1060 - 1067 (2004)
Published online: 24 October 2004; | doi:10.1038/nsmb847
Novel roles of TLR3 tyrosine phosphorylation and PI3 kinase in double-stranded RNA signaling
Saumendra N Sarkar1, Kristi L Peters1, Christopher P Elco1, Shuji Sakamoto2, Srabani Pal1
& Ganes C Sen1
1
Department of Molecular Biology, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
44195, USA.
2
Department of Immunology, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
44195, USA.
Correspondence should be addressed to Ganes C Sen seng@ccf.org
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.
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