title: The Ebola virus VP35 protein inhibits activation of interferon regulatory factor 3.
abstract: The Ebola virus VP35 protein was previously found to act as an interferon (IFN) antagonist which could complement growth of influenza delNS1 virus, a mutant influenza virus lacking the influenza virus IFN antagonist protein, NS1. The Ebola virus VP35 could also prevent the virus- or double-stranded RNA-mediated transcriptional activation of both the beta IFN (IFN-beta) promoter and the IFN-stimulated ISG54 promoter (C. Basler et al., Proc. Natl. Acad. Sci. USA 97:12289-12294, 2000). We now show that VP35 inhibits virus infection-induced transcriptional activation of IFN regulatory factor 3 (IRF-3)-responsive mammalian promoters and that VP35 does not block signaling from the IFN-alpha/beta receptor. The ability of VP35 to inhibit this virus-induced transcription correlates with its ability to block activation of IRF-3, a cellular transcription factor of central importance in initiating the host cell IFN response. We demonstrate that VP35 blocks the Sendai virus-induced activation of two promoters which can be directly activated by IRF-3, namely, the ISG54 promoter and the ISG56 promoter. Further, expression of VP35 prevents the IRF-3-dependent activation of the IFN-alpha4 promoter in response to viral infection. The inhibition of IRF-3 appears to occur through an inhibition of IRF-3 phosphorylation. VP35 blocks virus-induced IRF-3 phosphorylation and subsequent IRF-3 dimerization and nuclear translocation. Consistent with these observations, Ebola virus infection of Vero cells activated neither transcription from the ISG54 promoter nor nuclear accumulation of IRF-3. These data suggest that in Ebola virus-infected cells, VP35 inhibits the induction of antiviral genes, including the IFN-beta gene, by blocking IRF-3 activation.
authors.affiliation: Department of Microbiology, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029, USA. chris.basler@mssm.edu
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Basler
authors.forename: Andrea
authors.initials: A
authors.lastname: Mikulasova
authors.forename: Luis
authors.initials: L
authors.lastname: Martinez-Sobrido
authors.forename: Jason
authors.initials: J
authors.lastname: Paragas
authors.forename: Elke
authors.initials: E
authors.lastname: Mühlberger
authors.forename: Mike
authors.initials: M
authors.lastname: Bray
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Klenk
authors.forename: Peter
authors.initials: P
authors.lastname: Palese
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
mesh_terms: D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism*; D029043:Ebolavirus / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins / Q000502:physiology*; D010766:Phosphorylation; D029082:Sendai virus / Q000472:pathogenicity; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014709:Vero Cells; D014758:Viral Core Proteins / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins; D014157:Transcription Factors; D014758:Viral Core Proteins; C084818:nucleoprotein VP35, Ebola virus; D016899:Interferon-beta