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dc.contributor.authorGonzalez-Perez, Ana Cristina
dc.contributor.authorStempel, Markus
dc.contributor.authorWyler, Emanuel
dc.contributor.authorUrban, Christian
dc.contributor.authorPiras, Antonio
dc.contributor.authorHennig, Thomas
dc.contributor.authorGanskih, Sabina
dc.contributor.authorWei, Yuanjie
dc.contributor.authorHeim, Albert
dc.contributor.authorLandthaler, Markus
dc.contributor.authorPichlmair, Andreas
dc.contributor.authorDölken, Lars
dc.contributor.authorMunschauer, Mathias
dc.contributor.authorErhard, Florian
dc.contributor.authorBrinkmann, Melanie M
dc.date.accessioned2021-07-01T11:55:54Z
dc.date.available2021-07-01T11:55:54Z
dc.date.issued2021-05-04
dc.identifier.citationmBio 12:e02683-20. https://doi.org/10.1128/mBio.02683-20.en_US
dc.identifier.pmid33947766
dc.identifier.doi10.1128/mBio.02683-20
dc.identifier.urihttp://hdl.handle.net/10033/622916
dc.description.abstractInterferon-stimulated gene products (ISGs) play a crucial role in early infection control. The ISG zinc finger CCCH-type antiviral protein 1 (ZAP/ZC3HAV1) antagonizes several RNA viruses by binding to CG-rich RNA sequences, whereas its effect on DNA viruses is less well understood. Here, we decipher the role of ZAP in the context of human cytomegalovirus (HCMV) infection, a β-herpesvirus that is associated with high morbidity in immunosuppressed individuals and newborns. We show that expression of the two major isoforms of ZAP, ZAP-S and ZAP-L, is induced during HCMV infection and that both negatively affect HCMV replication. Transcriptome and proteome analyses demonstrated that the expression of ZAP results in reduced viral mRNA and protein levels and decelerates the progression of HCMV infection. Metabolic RNA labeling combined with high-throughput sequencing (SLAM-seq) revealed that most of the gene expression changes late in infection result from the general attenuation of HCMV. Furthermore, at early stages of infection, ZAP restricts HCMV by destabilizing a distinct subset of viral mRNAs, particularly those from the previously uncharacterized UL4-UL6 HCMV gene locus. Through enhanced cross-linking immunoprecipitation and sequencing analysis (eCLIP-seq), we identified the transcripts expressed from this HCMV locus as the direct targets of ZAP. Moreover, our data show that ZAP preferentially recognizes not only CG, but also other cytosine-rich sequences, thereby expanding its target specificity. In summary, this report is the first to reveal direct targets of ZAP during HCMV infection, which strongly indicates that transcripts from the UL4-UL6 locus may play an important role for HCMV replication.IMPORTANCE Viral infections have a large impact on society, leading to major human and economic losses and even global instability. So far, many viral infections, including human cytomegalovirus (HCMV) infection, are treated with a small repertoire of drugs, often accompanied by the occurrence of resistant mutants. There is no licensed HCMV vaccine in sight to protect those most at risk, particularly immunocompromised individuals or pregnant women who might otherwise transmit the virus to the fetus. Thus, the identification of novel intervention strategies is urgently required. In this study, we show that ZAP decelerates the viral gene expression cascade, presumably by selectively handpicking a distinct set of viral transcripts for degradation. Our study illustrates the potent role of ZAP as an HCMV restriction factor and sheds light on a possible role for UL4 and/or UL5 early during infection, paving a new avenue for the exploration of potential targets for novel therapies.en_US
dc.language.isoenen_US
dc.publisherASMen_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectDNA virusen_US
dc.subjectHCMVen_US
dc.subjectISGen_US
dc.subjectZAPen_US
dc.subjectZC3HAV1en_US
dc.subjectantiviralen_US
dc.subjectherpesvirusen_US
dc.subjecthuman cytomegalovirusen_US
dc.subjectinnate immunityen_US
dc.subjectinterferonsen_US
dc.subjectmRNA degradationen_US
dc.subjectpattern recognition receptorsen_US
dc.subjectzinc finger proteinsen_US
dc.titleThe Zinc Finger Antiviral Protein ZAP Restricts Human Cytomegalovirus and Selectively Binds and Destabilizes Viral / Transcripts.en_US
dc.typeArticleen_US
dc.identifier.eissn2150-7511
dc.contributor.departmentHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.en_US
dc.identifier.journalmBioen_US
dc.source.volume12
dc.source.issue3
refterms.dateFOA2021-07-01T11:55:54Z
dc.source.journaltitlemBio
dc.source.countryUnited States


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Attribution 4.0 International
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