Dissecting Herpes Simplex Virus 1-Induced Host Shutoff at the RNA Level
Caroline C. Friedel, Adam W. Whisnant, Lara Djaković, Andrzej Rutkowski, Marie-Sophie Friedl, Michael Kluge, James C. Williamson, Somesh Sai, Ramón Vidal, Sascha Sauer, Thomas Hennig, Arnhild Grothey, Andrea Milić, Bhupesh K. Prusty, Paul J. Lehner, Nicholas J. Matheson, Florian Erhard, Lars Dölken
Abstract
The HSV-1 virion host shutoff ( 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 infections, confirmed DUX4 as a key transcriptional regulator in HSV-1 infection, and identified vhs -dependent transcriptional downregulation 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 8 h p.i. for many of the respective genes.