title: Z proteins of New World arenaviruses bind RIG-I and interfere with type I interferon induction.
abstract: The retinoic acid-inducible gene I product (RIG-I) is a cellular sensor of RNA virus infection that regulates the cellular beta interferon (IFN-beta) response. The nucleoproteins (NP) of arenaviruses are reported to antagonize the IFN response by inhibiting interferon regulatory factor 3 (IRF-3). Here, we demonstrate that the Z proteins of four New World (NW) arenaviruses, Guanarito virus (GTOV), Junin virus (JUNV), Machupo virus (MAVC), and Sabia virus (SABV), bind to RIG-I, resulting in downregulation of the IFN-beta response. We show that expression of the four NW arenavirus Z proteins inhibits IFN-beta mRNA induction in A549 cells in response to RNA bearing 5' phosphates (5'pppRNA). NW arenavirus Z proteins interact with RIG-I in coimmunoprecipitation studies and colocalize with RIG-I. Furthermore, expression of Z proteins interferes with the interaction between RIG-I and MAVS. Z expression also impedes the nuclear factor kappa light chain enhancer of activated B cells (NF-kappaB) and IRF-3 activation. Our results indicate that NW arenavirus Z proteins, but not Z protein of the Old World (OW) arenavirus lymphocytic choriomeningitis virus (LCMV) or Lassa virus, bind to RIG-I and inhibit downstream activation of the RIG-I signaling pathway, preventing the transcriptional induction of IFN-beta.
authors.affiliation: Center for Infection and Immunity, Mailman School of Public Health, Columbia University, 722 West 168th Street, New York, NY 10032, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Fan
authors.forename: Thomas
authors.initials: T
authors.lastname: Briese
authors.forename: W Ian
authors.initials: WI
authors.lastname: Lipkin
mesh_terms: D006477:Arenaviruses, New World / Q000276:immunology* / Q000472:pathogenicity* / Q000502:physiology; D001483:Base Sequence; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic; D015398:Signal Transduction; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D014764:Viral Proteins; D016899:Interferon-beta; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases