title: The mengovirus leader protein blocks interferon-alpha/beta gene transcription and inhibits activation of interferon regulatory factor 3.
abstract: Viral infection of mammalian cells triggers the synthesis and secretion of type I interferons (i.e. IFN-alpha/beta), which induce the transcription of genes that cause cells to adopt an antiviral state. Many viruses have adapted mechanisms to evade IFN-alpha/beta-mediated responses. The leader protein of mengovirus, a picornavirus, has been implicated as an IFN-alpha/beta antagonist. Here, we show that the leader inhibits the transcription of IFN-alpha/beta and that both the presence of a zinc finger motif in its N-terminus and phosphorylation of threonine-47 are required for this function. Transcription of IFN-alpha/beta genes relies on the activity of a number of transcription factors, including interferon regulatory factor 3 (IRF-3). We show that the leader interferes with the transactivation activity of IRF-3 by interfering with its dimerization. Accordingly, mutant viruses with a disturbed leader function were impaired in their ability to suppress IFN-alpha/beta transcription in vivo. By consequence, the leader mutant viruses had an impaired ability to replicate and spread in normal mice but not in IFNAR-KO mice, which are incapable of mounting an IFN-alpha/beta-dependent antiviral response. These results suggest that the leader, by suppressing IRF3-mediated IFN-alpha/beta production, plays an important role in replication and dissemination of mengovirus in its host.
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Stanleyson V
authors.initials: SV
authors.lastname: Hato
authors.forename: Celine
authors.initials: C
authors.lastname: Ricour
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Schulte
authors.forename: Kjerstin H W
authors.initials: KH
authors.lastname: Lanke
authors.forename: Mike
authors.initials: M
authors.lastname: de Bruijni
authors.forename: Jan
authors.initials: J
authors.lastname: Zoll
authors.forename: Willem J G
authors.initials: WJ
authors.lastname: Melchers
authors.forename: Thomas
authors.initials: T
authors.lastname: Michiels
authors.forename: Frank J M
authors.initials: FJ
authors.lastname: van Kuppeveld
mesh_terms: D000818:Animals; D018188:Cardiovirus Infections / Q000276:immunology; D019281:Dimerization; D015536:Down-Regulation; D005260:Female; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors*; D016898:Interferon-alpha / Q000096:biosynthesis*; D016899:Interferon-beta / Q000096:biosynthesis*; D008574:Mengovirus / Q000235:genetics / Q000254:growth & development / Q000276:immunology*; D051379:Mice; D016019:Survival Analysis; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*; D014774:Virulence; D014779:Virus Replication / Q000276:immunology
chemical_list: D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha; D014764:Viral Proteins; D016899:Interferon-beta