title: Influenza A virus polymerase inhibits type I interferon induction by binding to interferon beta promoter stimulator 1.
abstract: Type I interferons (IFNs) are known to be critical factors in the activation of host antiviral responses and are also important in protection from influenza A virus infection. Especially, the RIG-I- and IPS-1-mediated intracellular type I IFN-inducing pathway is essential in the activation of antiviral responses in cells infected by influenza A virus. Previously, it has been reported that influenza A virus NS1 is involved in the inhibition of this pathway. We show in this report that the influenza A virus utilizes another critical inhibitory mechanism in this pathway. In fact, the viral polymerase complex exhibited an inhibitory activity on IFNβ promoter activation mediated by RIG-I and IPS-1, and this activity was not competitive with the function of NS1. Co-immunoprecipitation analysis revealed that each polymerase subunit bound to IPS-1 in mammalian cells, and each subunit inhibited the activation of IFNβ promoter by IPS-1 independently. In addition, by a combinational expression of each polymerase subunit, IPS-1-induced activation of IFNβ promoter was more efficiently inhibited by the expression of PB2 or PB2-containing complex. Moreover, the expression of PB2 inhibited the transcription of the endogenous IFNβ gene induced after influenza A virus infection. These findings demonstrate that the viral polymerase plays an important role for regulating host anti-viral response through the binding to IPS-1 and inhibition of IFNβ production.
authors.affiliation: Department of Bioresources, hHokkaido University Research Center for Zoonosis Control, North 20, West 10 Kita-ku, Sapporo, Hokkaido 001-0020, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwai
authors.forename: Takuya
authors.initials: T
authors.lastname: Shiozaki
authors.forename: Taro
authors.initials: T
authors.lastname: Kawai
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
authors.forename: Ayato
authors.initials: A
authors.lastname: Takada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kida
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Miyazaki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D012321:DNA-Directed RNA Polymerases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009980:Influenza A virus / Q000201:enzymology*; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000502:physiology; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C085820:INS1 protein, influenza virus; D007370:Interferon Type I; C505371:MAVS protein, human; C061290:PA protein, influenza viruses; C057027:PB2 protein, Influenzavirus A; D011971:Receptors, Immunologic; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C077346:influenza virus polymerase basic protein 1; D016899:Interferon-beta; D012324:RNA-Dependent RNA Polymerase; D012321:DNA-Directed RNA Polymerases; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases