title: Phosphatidylinositol-3-kinase and Akt are required for RIG-I-mediated anti-viral signalling through cross-talk with IPS-1.
abstract: Retinoic acid-inducible gene I (RIG-I) is a cytosolic pattern-recognition receptor that recognizes viruses and triggers anti-viral immune responses. Activation of intracellular RIG-I signalling is mediated through interferon-β (IFN-β) promoter stimulator-1 (IPS-1), an adaptor of RIG-I, which induces IFN regulatory factor (IRF) 3 activation and type I IFN expression. The phosphatidylinositol-3-kinase (PI3K) and Akt pathway is activated in host immune cells upon viral infection. However, the mechanism as to how they work in RIG-I signalling has not been fully elucidated. Therefore, we investigated the role of PI3K and Akt in the regulation of RIG-I-mediated IRF3 activation and type I IFN expression in macrophages. Our results show that Sendai virus infection, which is recognized by RIG-I, led to IRF3 activation and IFN-β expression and these responses were attenuated by the PI3K inhibitor (LY294002) and an Akt dominant-negative mutant in the macrophage cell line(RAW264.7). IRF3 phosphorylation and dimerization as well as IFN-β expression induced by a synthetic RIG-I agonist, short poly(I:C), were suppressed by LY294002 or siRNA-Akt in bone marrow-derived macrophages. Suppression of PI3K and Akt using a dominant-negative mutant and siRNA knockdown resulted in attenuation of IRF3 activation and IFN-β expression induced by RIG-I itself or its adaptor, IPS-1. Association of Akt with IPS-1 increased with short poly(I:C) stimulation and required the pleckstrin homology domain of Akt and caspase-recruitment domain in IPS-1. Collectively, our results show that PI3K and Akt are required downstream of IPS-1 for RIG-I-mediated anti-viral immune responses. The results describe a novel, interactive relationship between RIG-I downstream signalling molecules resulting in efficient anti-viral immunity.
authors.affiliation: College of Pharmacy, Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, Korea.
authors.forename: Sang Hyeon
authors.initials: SH
authors.lastname: Yeon
authors.forename: Moon Jung
authors.initials: MJ
authors.lastname: Song
authors.forename: Hye-Ri
authors.initials: HR
authors.lastname: Kang
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000276:immunology*; D019281:Dimerization; D004789:Enzyme Activation / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology; D050838:Interferon Regulatory Factor-3 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000276:immunology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011070:Poly I-C / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D010253:Respirovirus Infections / Q000276:immunology; D029082:Sendai virus / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000998:Antiviral Agents; D002867:Chromones; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D004791:Enzyme Inhibitors; D007369:Interferon Inducers; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D009025:Morpholines; D058539:Phosphatidylinositol 3-Kinase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011070:Poly I-C; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; C512612:MAVS protein, mouse; C494233:Irf3 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C503356:Ddx58 protein, mouse
keywords: innate immunity; macrophages; pattern-recognition receptor; type I interferon; virus infection