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dc.contributor.authorFriedel, Caroline C
dc.contributor.authorWhisnant, Adam W
dc.contributor.authorDjakovic, Lara
dc.contributor.authorRutkowski, Andrzej J
dc.contributor.authorFriedl, Marie-Sophie
dc.contributor.authorKluge, Michael
dc.contributor.authorWilliamson, James C
dc.contributor.authorSai, Somesh
dc.contributor.authorVidal, Ramon Oliveira
dc.contributor.authorSauer, Sascha
dc.contributor.authorHennig, Thomas
dc.contributor.authorGrothey, Arnhild
dc.contributor.authorMilić, Andrea
dc.contributor.authorPrusty, Bhupesh K
dc.contributor.authorLehner, Paul J
dc.contributor.authorMatheson, Nicholas J
dc.contributor.authorErhard, Florian
dc.contributor.authorDölken, Lars
dc.identifier.citationJ Virol. 2020 Nov 4:JVI.01399-20. doi: 10.1128/JVI.01399-20.en_US
dc.description.abstractHerpes simplex virus 1 (HSV-1) induces a profound host shut-off during lytic infection. The virion host shut-off (vhs) protein plays a key role in this process by efficiently cleaving host and viral mRNAs. Furthermore, the onset of viral DNA replication is accompanied by a rapid decline in host transcriptional activity. To dissect relative contributions of both mechanisms and elucidate gene-specific host transcriptional responses throughout the first 8h of lytic HSV-1 infection, we employed RNA-seq of total, newly transcribed (4sU-labelled) and chromatin-associated RNA in wild-type (WT) and Δvhs infection of primary human fibroblasts. Following virus entry, vhs activity rapidly plateaued at an elimination rate of around 30% of cellular mRNAs per hour until 8h p.i. In parallel, host transcriptional activity dropped to 10-20%. While the combined effects of both phenomena dominated infection-induced changes in total RNA, extensive gene-specific transcriptional regulation was observable in chromatin-associated RNA and was surprisingly concordant between WT and Δvhs infection. Both induced strong transcriptional up-regulation of a small subset of genes that were poorly expressed prior to infection but already primed by H3K4me3 histone marks at their promoters. Most interestingly, analysis of chromatin-associated RNA revealed vhs-nuclease-activity-dependent transcriptional down-regulation of at least 150 cellular genes, in particular of many integrin adhesome and extracellular matrix components. This was accompanied by a vhs-dependent reduction in protein levels by 8h p.i. for many of these genes. In summary, our study provides a comprehensive picture of the molecular mechanisms that govern cellular RNA metabolism during the first 8h of lytic HSV-1 infection.IMPORTANCE The HSV-1 virion host shut-off (vhs) protein efficiently cleaves both host and viral mRNAs in a translation-dependent manner. In this study, we model and quantify changes in vhs activity as well as virus-induced global loss of host transcriptional activity during productive HSV-1 infection. In general, HSV-1-induced alterations in total RNA levels were dominated by these two global effects. In contrast, chromatin-associated RNA depicted gene-specific transcriptional changes. This revealed highly concordant transcriptional changes in WT and Δvhs infection, confirmed DUX4 as a key transcriptional regulator in HSV-1 infection and depicted vhs-dependent, transcriptional down-regulation of the integrin adhesome and extracellular matrix components. The latter explained seemingly gene-specific effects previously attributed to vhs-mediated mRNA degradation and resulted in a concordant loss in protein levels by 8h p.i. for many of the respective genes.en_US
dc.publisherAmerican Society for Microbilogy (ASM)en_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.titleDissecting Herpes Simplex Virus 1-Induced Host Shutoff at the RNA Level.en_US
dc.contributor.departmentHIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany.en_US
dc.identifier.journalJournal of virologyen_US
dc.source.journaltitleJournal of virology
dc.source.countryUnited States

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