title: The zinc finger antiviral protein acts synergistically with an interferon-induced factor for maximal activity against alphaviruses.
abstract: Type I interferons (IFNs) signal through specific receptors to mediate expression of genes, which together confer a cellular antiviral state. Overexpression of the zinc finger antiviral protein (ZAP) imparts a cellular antiviral state against Retroviridae, Togaviridae, and Filoviridae virus family members. Since ZAP expression is induced by IFN, we utilized Sindbis virus (SINV) to investigate the role of other IFN-induced factors in ZAP's inhibitory potential. Overexpressed ZAP did not inhibit virion production or SINV-induced cell death in BHK cells deficient in IFN production (and thus IFN signaling), suggesting a role for an IFN-induced factor in ZAP's activity. IFN pretreatment in the presence of ZAP resulted in greater inhibition than IFN alone. Using mouse embryo fibroblast (MEF) cells deficient in Stat1, we showed that signaling through the IFN receptor is necessary for IFN's enhancement of ZAP activity. Unlike in BHK cells, however, overexpressed ZAP exhibited antiviral activity in the absence of IFN. In wild-type MEFs with an intact Stat1 gene, IFN pretreatment synergized with ZAP to generate a potent antiviral response. Despite failing to inhibit SINV virion production and virus-induced cell death in BHK cells, ZAP inhibited translation of the incoming viral RNA. IFN pretreatment synergized with ZAP to further block protein expression from the incoming viral genome. We further show that silencing of IFN-induced ZAP reduces IFN efficacy. Our findings demonstrate that ZAP can synergize with another IFN-induced factor(s) for maximal antiviral activity and that ZAP's intrinsic antiviral activity on virion production and cell survival can have cell-type-specific outcomes.
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, Box 64, 1230 York Avenue, New York, NY 10065, USA. macdonm@rockefeller.edu
authors.forename: Margaret R
authors.initials: MR
authors.lastname: MacDonald
authors.forename: Erica S
authors.initials: ES
authors.lastname: Machlin
authors.forename: Owen R
authors.initials: OR
authors.lastname: Albin
authors.forename: David E
authors.initials: DE
authors.lastname: Levy
mesh_terms: D000524:Alphavirus / Q000187:drug effects / Q000472:pathogenicity; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D004357:Drug Synergism; D005347:Fibroblasts / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins; D051381:Rats; D012845:Sindbis Virus / Q000187:drug effects* / Q000472:pathogenicity*; D016335:Zinc Fingers
chemical_list: D002352:Carrier Proteins; D016898:Interferon-alpha; D011506:Proteins; D016601:RNA-Binding Proteins; C465959:Zc3hav1 protein, rat