Abstract
Viruses are by definition fully dependent on the cellular translation machinery, and develop diverse mechanisms to co-opt this machinery for their own benefit. Unlike many viruses, human cytomegalovirus (HCMV) does suppress the host translation machinery, and the extent to which translation machinery contributes to the overall pattern of viral replication and pathogenesis remains elusive. Here, we combine RNA sequencing and ribosomal profiling analyses to systematically address this question. By simultaneously examining the changes in transcription and translation along HCMV infection, we uncover extensive transcriptional control that dominates the response to infection, but also diverse and dynamic translational regulation for subsets of host genes. We were also able to show that, at late time points in infection, translation of viral mRNAs is higher than that of cellular mRNAs. Lastly, integration of our translation measurements with recent measurements of protein abundance enabled comprehensive identification of dozens of host proteins that are targeted for degradation during HCMV infection. Since targeted degradation indicates a strong biological importance, this approach should be applicable for discovering central host functions during viral infection. Our work provides a framework for studying the contribution of transcription, translation and degradation during infection with any virus.
Highlights
Human cytomegalovirus (HCMV) is a ubiquitous pathogen, infecting the majority of the human population worldwide, leading to severe diseases in newborns and immunocompromised adults
Viruses are fully dependent on the cellular translation machinery, and develop diverse mechanisms to co-opt it for their own benefit
Simultaneous monitoring of RNA levels and translation during HCMV infection To gain a detailed view of the changes that occur in host genes transcription and translation over the course of HCMV infection, we infected human foreskin fibroblasts (HFF) with the Merlin HCMV strain and harvested cells at 5, 12, 24 and 72 hours post infection
Summary
Human cytomegalovirus (HCMV) is a ubiquitous pathogen, infecting the majority of the human population worldwide, leading to severe diseases in newborns and immunocompromised adults. The use of microarrays revealed many biological pathways that are significantly altered during infection and established an important progress in our understanding of how HCMV exploits cellular pathways during infection [6,7,8,9,10,11] These studies helped to reveal numerous pathways that are elevated during infection and are important for viral propagation such as cell cycle, DNA damage, transcription and translation factors and energy production. Advancement in mass-spectrometry methods had been used to quantify the cell proteome along HCMV infection giving a wider view on the pathways that are altered during infection [12] This method was used to predict natural killer (NK) and T cells ligands by identifying cell surface molecules which are downregulated during HCMV infection [12]. Expression of pUL38, a virally encoded mTORC1-activator sufficed to partially recapitulate these translational alterations in uninfected cells, demonstrating that some of the effect is mediated by mTORC1 activation [17]
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