title: Phosphatidylinositol-3-kinase (PI3K) is activated by influenza virus vRNA via the pathogen pattern receptor Rig-I to promote efficient type I interferon production.
abstract: The phosphatidylinositol-3-kinase (PI3K) was identified to be activated upon influenza A virus (IAV) infection. An early and transient induction of PI3K signalling is caused by viral attachment to cells and promotes virus entry. In later phases of infection the kinase is activated by the viral NS1 protein to prevent premature apoptosis. Besides these virus supporting functions, it was suggested that PI3K signalling is involved in dsRNA and IAV induced antiviral responses by enhancing the activity of interferon regulatory factor-3 (IRF-3). However, molecular mechanisms of activation remained obscure. Here we show that accumulation of vRNA in cells infected with influenza A or B viruses results in PI3K activation. Furthermore, expression of the RNA receptors Rig-I and MDA5 was increased upon stimulation with virion extracted vRNA or IAV infection. Using siRNA approaches, Rig-I was identified as pathogen receptor necessary for influenza virus vRNA sensing and subsequent PI3K activation in a TRIM25 and MAVS signalling dependent manner. Rig-I induced PI3K signalling was further shown to be essential for complete IRF-3 activation and consequently induction of the type I interferon response. These data identify PI3K as factor that is activated as part of the Rig-I mediated anti-pathogen response to enhance expression of type I interferons.
authors: Institute of Molecular Virology, ZMBE, Von Esmarch-Str. 56, D-48149 Muenster, Germany.
authors: Eike R
authors: ER
authors: Hrincius
authors: Rüdiger
authors: R
authors: Dierkes
authors: Darisuren
authors: D
authors: Anhlan
authors: Viktor
authors: V
authors: Wixler
authors: Stephan
authors: S
authors: Ludwig
authors: Christina
authors: C
authors: Ehrhardt
mesh_terms: D000818:Animals; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000276:immunology / Q000378:metabolism*; D004285:Dogs; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D009981:Influenza B virus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D007251:Influenza, Human / Q000276:immunology* / Q000821:virology; D050838:Interferon Regulatory Factor-3 / Q000276:immunology / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology*; D000072640:Interferon-Induced Helicase, IFIH1; D058539:Phosphatidylinositol 3-Kinase / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011971:Receptors, Immunologic; D051192:Receptors, Pattern Recognition / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014779:Virus Replication
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D034741:RNA, Small Interfering; D012367:RNA, Viral; D011971:Receptors, Immunologic; D051192:Receptors, Pattern Recognition; D058539:Phosphatidylinositol 3-Kinase; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1