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

病毒感染人类细胞，并在其复制策略中利用广泛的细胞途径，利用它们将细胞转化为病毒生产。病毒产生的许多蛋白质与细胞蛋白质相似，并执行相同的活动来帮助病毒复制。因此，这些病毒蛋白可以作为尚未表征的细胞活动的极好模型，并有助于解开细胞中的复杂途径。在细胞中，RNA信息由细胞核中的基因产生，然后被运送到细胞质中翻译成蛋白质。一种叫做核糖核酸内切酶的重要酶参与调节细胞内RNA信息的水平，以控制在任何时候合成的蛋白质的数量和特异性。这些酶在不同的过程中发挥作用，如对压力或病毒感染的反应，或炎症的调节。因此，它们对于维持平衡的细胞环境和保持细胞健康至关重要。此外，一些核糖核酸内切酶的突变与一系列疾病有关，包括遗传性血液病、癌症和衰老引起的变化。包括疱疹病毒和流感病毒在内的许多病毒也制造核糖核酸内切酶来调节细胞内制造的蛋白质。这一建议涉及单纯疱疹病毒核糖核酸内切酶，称为vhs。我们发现，这种单一的病毒蛋白不仅能够消除RNA信息，而且还能将许多RNA信息捕获在细胞核中，使它们产生但无法翻译成蛋白质，从而有效地调节细胞中蛋白质的产生。在分子水平上，vhs的作用模式与其细胞对应物的范围相似。因此，使用vhs作为模型系统，我们的目标是揭示由vhs发起的复杂事件集。特别是，我们的目标是使用最先进的技术来定义RNA信息的核种群如何在全球水平上响应vhs活动而变化。我们还将通过探索vhs对细胞核到细胞质的输出通路的影响来研究这些vhs诱导的变化的机制。最后，我们将确定如何在细胞内控制vhs蛋白本身，以确保其表达对细胞不致命。这项研究将促进目前对这些酶在病毒感染细胞和健康细胞中调节蛋白质生产中的作用的理解。此外，它还将有利于对发现这些酶有缺陷的疾病的其他研究，从而影响基础科学和转化科学。

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.