title: A Kaposi's sarcoma-associated herpesviral protein inhibits virus-mediated induction of type I interferon by blocking IRF-7 phosphorylation and nuclear accumulation.
abstract: Interferons constitute the earliest immune response against viral infection. They elicit antiviral effects as well as multiple biological responses involved in cell growth regulation and immune activation. Because the interferon-induced cellular antiviral response is the primary defense mechanism against viral infection, many viruses have evolved strategies to antagonize the inhibitory effects of interferon. Here, we demonstrate a strategy that Kaposi's sarcoma-associated herpesvirus uses to block virus-mediated induction of type I interferon. We found that a viral immediate-early protein, namely ORF45, interacts with cellular interferon-regulatory factor 7 (IRF-7). In consequence, IRF-7 phosphorylation is inhibited and the accumulation of IRF-7 in the nucleus in response to viral infection is blocked. IRF-7 is a transcription regulator that is responsible for virus-mediated activation of type I interferon genes. By blocking the phosphorylation and nuclear translocation of IRF-7, ORF45 efficiently inhibits the activation of interferon alpha and beta genes during viral infection. Inhibition of interferon gene expression through a viral protein blocking the activation and nuclear translocation of a crucial transcription factor is a novel mechanism for viral immune evasion.
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA 19104, USA.
authors.forename: Fan Xiu
authors.initials: FX
authors.lastname: Zhu
authors.forename: Sonya M
authors.initials: SM
authors.lastname: King
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Smith
authors.forename: David E
authors.initials: DE
authors.lastname: Levy
authors.forename: Yan
authors.initials: Y
authors.lastname: Yuan
mesh_terms: D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D016366:Open Reading Frames; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D029082:Sendai virus / Q000378:metabolism; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques; D014764:Viral Proteins / Q000737:chemistry* / Q000502:physiology*
chemical_list: D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C494234:IRF7 protein, human; D017874:Immediate-Early Proteins; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D008164:Luminescent Proteins; C456286:ORF45 protein, Kaposi's sarcoma-associated herpesvirus; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; D049452:Green Fluorescent Proteins; D008156:Luciferases; D005982:Glutathione Transferase