Dissecting Herpes Simplex Virus 1-Induced Host Shutoff at the RNA Level.
dc.contributor.author | Friedel, Caroline C | |
dc.contributor.author | Whisnant, Adam W | |
dc.contributor.author | Djakovic, Lara | |
dc.contributor.author | Rutkowski, Andrzej J | |
dc.contributor.author | Friedl, Marie-Sophie | |
dc.contributor.author | Kluge, Michael | |
dc.contributor.author | Williamson, James C | |
dc.contributor.author | Sai, Somesh | |
dc.contributor.author | Vidal, Ramon Oliveira | |
dc.contributor.author | Sauer, Sascha | |
dc.contributor.author | Hennig, Thomas | |
dc.contributor.author | Grothey, Arnhild | |
dc.contributor.author | Milić, Andrea | |
dc.contributor.author | Prusty, Bhupesh K | |
dc.contributor.author | Lehner, Paul J | |
dc.contributor.author | Matheson, Nicholas J | |
dc.contributor.author | Erhard, Florian | |
dc.contributor.author | Dölken, Lars | |
dc.date.accessioned | 2020-11-24T12:15:46Z | |
dc.date.available | 2020-11-24T12:15:46Z | |
dc.date.issued | 2020-11-04 | |
dc.identifier.citation | J Virol. 2020 Nov 4:JVI.01399-20. doi: 10.1128/JVI.01399-20. | en_US |
dc.identifier.pmid | 33148793 | |
dc.identifier.doi | 10.1128/JVI.01399-20 | |
dc.identifier.uri | http://hdl.handle.net/10033/622606 | |
dc.description.abstract | Herpes 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.language.iso | en | en_US |
dc.publisher | American Society for Microbilogy (ASM) | en_US |
dc.rights | Attribution-NonCommercial-ShareAlike 4.0 International | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | * |
dc.title | Dissecting Herpes Simplex Virus 1-Induced Host Shutoff at the RNA Level. | en_US |
dc.type | Article | en_US |
dc.identifier.eissn | 1098-5514 | |
dc.contributor.department | HIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany. | en_US |
dc.identifier.journal | Journal of virology | en_US |
refterms.dateFOA | 2020-11-24T12:15:47Z | |
dc.source.journaltitle | Journal of virology | |
dc.source.country | United States |