title: ZAP inhibits murine gammaherpesvirus 68 ORF64 expression and is antagonized by RTA.
abstract: Zinc finger antiviral protein (ZAP) is an interferon-inducible host antiviral factor that specifically inhibits the replication of certain viruses, including HIV-1 and Ebola virus. ZAP functions as a dimer formed through intermolecular interactions of its N-terminal tails. ZAP binds directly to specific viral mRNAs and inhibits their expression by repressing translation and/or promoting degradation of the target mRNA. ZAP is not a universal antiviral factor, since some viruses grow normally in ZAP-expressing cells. It is not fully understood what determines whether a virus is susceptible to ZAP. We explored the interaction between ZAP and murine gammaherpesvirus 68 (MHV-68), whose life cycle has latent and lytic phases. We previously reported that ZAP inhibits the expression of M2, which is expressed mainly in the latent phase, and regulates MHV-68 latency in cultured cells. Here, we report that ZAP inhibits the expression of ORF64, a tegument protein that is expressed in the lytic phase and is essential for lytic replication. MHV-68 infection induced ZAP expression. However, ZAP did not inhibit lytic replication of MHV-68. We provide evidence showing that the antiviral activity of ZAP is antagonized by MHV-68 RTA, a critical viral transactivator expressed in the lytic phase. We further show that RTA inhibits the antiviral activity of ZAP by disrupting the N-terminal intermolecular interaction of ZAP. Our results provide an example of how a virus can escape ZAP-mediated immunity.
authors.affiliation: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, China.
authors.forename: Yifang
authors.initials: Y
authors.lastname: Xuan
authors.forename: Danyang
authors.initials: D
authors.lastname: Gong
authors.forename: Jing
authors.initials: J
authors.lastname: Qi
authors.forename: Chuanhui
authors.initials: C
authors.lastname: Han
authors.forename: Hongyu
authors.initials: H
authors.lastname: Deng
authors.forename: Guangxia
authors.initials: G
authors.lastname: Gao
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D018142:Gammaherpesvirinae / Q000235:genetics* / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016366:Open Reading Frames / Q000235:genetics*; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D017735:Virus Latency / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
chemical_list: D017874:Immediate-Early Proteins; C577263:M2 protein, murine gammaherpesvirus 68; D012333:RNA, Messenger; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D014764:Viral Proteins