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| Item Type: | Article |
|---|---|
| Title: | Dissecting herpes simplex virus 1-induced host shutoff at the RNA level |
| Creators Name: | Friedel, C.C. and Whisnant, A.W. and Djakovic, L. and Rutkowski, A.J. and Friedl, M.S. and Kluge, M. and Williamson, J.C. and Sai, S. and Vidal, R.O. and Sauer, S. and Hennig, T. and Grothey, A. and Milić, A. and Prusty, B.K. and Lehner, P.J. and Matheson, N.J. and Erhard, F. and Dölken, L. |
| 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. |
| Keywords: | Fibroblasts, Herpes Simplex, Human Herpesvirus 1, Protein Biosynthesis, Proteome, Ribonucleases, Transcriptome, Viral Gene Expression Regulation, Viral Proteins, Viral RNA, Virus Replication |
| Source: | Journal of Virology |
| ISSN: | 0022-538X |
| Publisher: | American Society for Microbiology |
| Volume: | 95 |
| Number: | 3 |
| Page Range: | e01399-20 |
| Date: | 13 January 2021 |
| Official Publication: | https://doi.org/10.1128/JVI.01399-20 |
| PubMed: | View item in PubMed |
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