Global Reprogramming of the Cellular Translational Landscape Facilitates Cytomegalovirus Replication

Caleb Mckinney,Jiri Zavadil,Christopher Bianco,Lora Shiflett,Stuart Brown,Ian Mohr

doi:10.1016/j.celrep.2013.11.045

Abstract

Unlike many viruses that suppress cellular protein synthesis, host mRNA translation and polyribosome formation are stimulated by human cytomegalovirus (HCMV). How HCMV impacts the translationally regulated cellular mRNA repertoire and its contribution to virus biology remains unknown. Using polysome profiling, we show that HCMV presides over the cellular translational landscape, selectively accessing the host genome to extend its own coding capacity and regulate virus replication. Expression of the HCMV UL38 mTORC1-activator partially recapitulates these translational alterations in uninfected cells. The signature of cellular mRNAs translationally stimulated by HCMV resembles pathophysiological states (such as cancer) where translation initiation factor levels or activity increase. In contrast, cellular mRNAs repressed by HCMV include those involved in differentiation and the immune response. Surprisingly, interfering with the virus-induced activation of cellular mRNA translation can either limit or enhance HCMV growth. The unanticipated extent to which HCMV specifically manipulates host mRNA translation may aid in understanding its association with complex inflammatory disorders and cancer.

Highlights

In addition to their absolute reliance on cellular ribosomes to produce viral polypeptides, viruses can profoundly impact host protein synthesis
Unlike viruses that shutoff cellular protein synthesis, polyribosome formation is stimulated and host mRNA translation proceeds uninterrupted in human cytomegalovirus (HCMV)-infected cells (Tanaka et al 1975; Stinski, 1977)
The signature of cellular mRNAs translationally-activated by HCMV, which encode a select suite of proteins critical for DNA damage response, proliferation, ribosome biogenesis, chromatin organization, organelle function and vesicle transport, resembles pathophysiological states where translation initiation factor levels or activity increase, including cancer

Summary

SUMMARY

Unlike many viruses that suppress cellular protein synthesis, host mRNA translation and polyribosome formation are stimulated by human cytomegalovirus (HCMV). How HCMV impacts the translationally-regulated cellular mRNA repertoire and its contribution to virus biology remains unknown. We show using polysome profiling that HCMV presides over the cellular translational landscape, selectively accessing the host genome to extend its own coding capacity and regulate virus replication. The signature of cellular mRNAs translationally-stimulated by HCMV resembles pathophysiological states where translation initiation factor levels or activity increase such as cancer. Interfering with the virus-induced activation of cellular mRNA translation can either limit or enhance HCMV growth. The unanticipated extent to which HCMV manipulates host mRNA translation may aid in understanding its association with complex inflammatory disorders and cancer

INTRODUCTION

RESULTS & DISCUSSION

EXPERIMENTAL PROCEDURES