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.
Sarkar
Saumendra N
SN
Department of Molecular Biology, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Peters
Kristi L
KL
Elco
Christopher P
CP
Sakamoto
Shuji
S
Pal
Srabani
S
Sen
Ganes C
GC
D021581:Active Transport, Cell Nucleus; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D019281:Dimerization; D015180:Electrophoresis, Gel, Two-Dimensional; D004789:Enzyme Activation; D006801:Humans; D047468:Immunoprecipitation; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000502:physiology*; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000502:physiology*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012330:RNA, Double-Stranded / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000737:chemistry; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction; D013912:Threonine / Q000737:chemistry; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014443:Tyrosine / Q000737:chemistry*
D008562:Membrane Glycoproteins; D012330:RNA, Double-Stranded; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D013912:Threonine; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases