Impact of a viral endoribonuclease on the nucleocytoplasmic compartmentalisation of the cellular transcriptome

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Viruses infect human cells and exploit a wide range of cellular pathways in their replication strategies, using them to their own advantage to turn the cell in to a virus production. Many proteins produced by viruses are similar to cellular proteins and perform equivalent activities to help the virus to replicate. As such, these virus proteins can act as excellent models for as yet uncharacterised cellular activities and help to unravel complex pathways in the cell. In the cell, RNA messages are made from genes in the nucleus and then transported to the cytoplasm to be translated in to proteins. Important enzymes called endoribonucleases are involved in regulating the levels of RNA message in the cell, to control the amount and specificity of protein being made at any one time. These enzymes have roles in diverse processes such as responses to stress or virus infection, or regulation of inflammation. As such, they are critical for maintaining a balanced cellular environment and keeping cells healthy. Moreover, mutations in a number of endoribonucleases have been linked to a range of diseases including inherited blood disorders, cancer and changes through ageing. Many viruses including herpesviruses and influenza viruses also make endoribonucleases to regulate the proteins that are being made within the cell. This proposal concerns the herpes simplex virus endoribonuclease called vhs. We have found that this single virus protein has the ability to not only eliminate RNA messages, but also to entrap many of them in the nucleus such that they are produced but not available for translation in to protein, thereby efficiently regulating protein production in the cell.At the molecular level, the vhs mode of action is similar to its range of cellular counterparts. Hence, using vhs as a model system, we aim to unravel the complex set of events initiated by vhs. In particular, we aim to use state-of-the-art technology to define how the nuclear population of RNA message changes on a global level in response to vhs activity. We will also investigate the mechanism of these vhs-induced changes by exploring its effect on export pathways from the nucleus to the cytoplasm. Finally, we will determine how the vhs protein itself is controlled within the cell to ensure that its expression is non-lethal to the cell.This study will advance current understanding of the role of these enzymes in the regulation of protein production in both virus infected and healthy cells. Moreover, it will benefit other studies on diseases where these enzymes have been found to be defective, thereby impacting both fundamental and translational science.