The battle for the 5' end: dissecting a novel virus-specific translation mechanism driven by eIF3

5端之战：剖析由eIF3驱动的新型病毒特异性翻译机制

• 批准号: BB/S006931/1
• 负责人: Nicolas Locker
• 金额: $ 51.34万
• 依托单位: University of Surrey
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS006931%2F1
• 关键词: battle; end; dissecting; novel; virus

Our aim is to understand a new mechanism of protein production by viruses of clinical and economical importance and examine how it contributes to escaping detection from the host. Cells within the body respond to external stimuli in many ways, the most common of which is via the regulation of gene expression. In response to external stresses such as infection, cells can pause protein synthesis, or translation, and thus the decoding of genetic information. This defense mechanism allows cells to survive by limiting the use of energy and nutrients that protein synthesis requires until the stress is resolved. It also blocks the spread of viruses as viruses are dependent on host cell resources to produce viral proteins and replicate. Because of this, viruses have developed strategies to produce their proteins using alternative mechanisms. Using different viruses as models, we have previously made significant advances in identifying new mechanisms that viruses use to manipulate the host cell by regulating translation. Viruses transmitted by mosquitoes represent a major burden on human and animal health. Among these, dengue virus is a prominent human health threat causing millions of infections every year worldwide, with no broadly effective or specific treatment. We previously showed that dengue virus infection results in a block in host protein synthesis, yet it remains a mystery how viral proteins are translated to support viral propagation. This is important because understanding how viruses hijack host resources can reveal a new Achilles' heel in the viral armour.Based on our results, we propose that dengue virus proteins are translated via a novel mechanism that uses a known cellular translation factor, eIF3, in a non-conventional manner to mediate translation. We also propose that this mechanism could help dengue virus escape detection by the host. Therefore, our objectives are to 1- characterize how eIF3 interacts with the viral RNA; 2- elucidate how this contributes to a new mechanism of translation and 3- establish how this mechanism competes with non-self detection of the viral RNA by the host. From this work we expect to advance our knowledge of how viruses take control of host resources to ensure viral proteins are made. This mechanism is novel, and we think it represents a new line of counterdefence evolved by viruses. Therefore, it can help identify new ways to inhibit virus replication and develop novel antiviral therapies for an important group of viruses. Understanding the fundamental mechanisms of gene regulation is important for virologists, but also for broader academic communities. It may also help us to appreciate better a basis of several pathologies, such as cancer or neurodegenerative diseases, that are linked to alternative translation mechanisms.

我们的目的是了解一种新的机制，蛋白质生产的病毒的临床和经济的重要性，并研究它如何有助于逃避检测从主机。体内的细胞以多种方式对外部刺激做出反应，其中最常见的是通过基因表达的调节。为了应对感染等外部压力，细胞可以暂停蛋白质合成或翻译，从而暂停遗传信息的解码。这种防御机制允许细胞通过限制蛋白质合成所需的能量和营养物质的使用来生存，直到压力得到解决。它还阻止病毒的传播，因为病毒依赖于宿主细胞资源来产生病毒蛋白和复制。正因为如此，病毒已经开发出了使用替代机制来生产其蛋白质的策略。使用不同的病毒作为模型，我们以前在确定病毒通过调节翻译来操纵宿主细胞的新机制方面取得了重大进展。蚊子传播的病毒是人类和动物健康的主要负担。其中，登革热病毒是一个突出的人类健康威胁，每年在全世界造成数百万人感染，没有广泛有效或特异性的治疗方法。我们先前表明，登革热病毒感染导致宿主蛋白质合成受阻，但病毒蛋白质如何翻译以支持病毒繁殖仍然是一个谜。这是很重要的，因为了解病毒如何劫持宿主资源可以揭示一个新的阿喀琉斯之踵在病毒armamel.Based上，我们的研究结果，我们提出，登革热病毒蛋白的翻译通过一种新的机制，使用一个已知的细胞翻译因子，eIF 3，在一个非常规的方式来介导翻译。我们还提出，这种机制可以帮助登革热病毒逃脱宿主的检测。因此，我们的目标是：1-表征eIF 3如何与病毒RNA相互作用; 2-阐明这如何有助于新的翻译机制; 3-建立这种机制如何与宿主对病毒RNA的非自我检测竞争。从这项工作中，我们希望推进我们对病毒如何控制宿主资源以确保病毒蛋白质产生的知识。这种机制是新颖的，我们认为它代表了病毒进化出的一种新的防御手段。因此，它可以帮助确定抑制病毒复制的新方法，并为一组重要的病毒开发新的抗病毒疗法。了解基因调控的基本机制对病毒学家很重要，但对更广泛的学术界也很重要。它还可以帮助我们更好地理解与替代翻译机制有关的几种病理学基础，如癌症或神经退行性疾病。

项目成果

A little less aggregation a little more replication: Viral manipulation of stress granules.

• DOI: 10.1002/wrna.1741
• 发表时间: 2023-01
• 期刊: Wiley interdisciplinary reviews. RNA

An interaction between eIF4A3 and eIF3g drives the internal initiation of translation.

• DOI: 10.1093/nar/gkad763
• 发表时间: 2023-11-10
• 期刊: Nucleic acids research
• 影响因子: 14.9