title: The second messenger phosphatidylinositol-5-phosphate facilitates antiviral innate immune signaling.
abstract: Innate immune receptors, notably Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), sense viral infection and activate transcription factors, including interferon regulatory factor-3 (IRF3), to induce type I interferon (IFN). We demonstrate that the lipid phosphatidylinositol-5-phosphate (PtdIns5P) is increased upon viral infection and facilitates type I IFN production by binding to IRF3 and its upstream kinase TBK1 and promoting TBK1-mediated IRF3 phosphorylation and activation. Additionally, we determine that PtdIns5P is produced through the kinase PIKfyve, which phosphorylates PtdIns to generate PtdIns5P. Accordingly, PIKfyve knockdown or pharamoclogical inhibition decreases PtdIns5P levels and type I IFN production after TLR or RLR stimulation, and results in increased viral replication. A synthetic PtdIns5P, C8-PtdIns5P, promotes IRF3 phosphorylation and cytokine production in dendritic cells and acts as an adjuvant to boost immune responses in immunized mice. Thus, PtdIns5P produced during viral infection is a second messenger that targets the TBK1-IRF3 axis to elicit antiviral immunity.
authors: Laboratory of Molecular Immunobiology, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
authors: Takumi
authors: T
authors: Kawasaki
authors: Naoki
authors: N
authors: Takemura
authors: Daron M
authors: DM
authors: Standley
authors: Shizuo
authors: S
authors: Akira
authors: Taro
authors: T
authors: Kawai
mesh_terms: D000818:Animals; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011971:Receptors, Immunologic; D015290:Second Messenger Systems; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D014780:Viruses / Q000276:immunology*
chemical_list: D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D017346:Protein Serine-Threonine Kinases; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; C494232:IRF3 protein, human; C113567:phosphatidylinositol 5-phosphate; C492139:PIKFYVE protein, human; C403191:TBK1 protein, human; C452820:RIGI protein, human