Enemy at the gate: a novel mechanism of paracrine stress granule induction by viruses

门口的敌人：病毒诱导旁分泌应激颗粒的新机制

• 批准号: BB/P018068/1
• 负责人: Nicolas Locker
• 金额: $ 50.91万
• 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: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP018068%2F1
• 关键词: Enemy; gate; novel; mechanism; paracrine

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 stress such as infection, cells can pause protein synthesis, or translation, and thus the decoding of genetic information, by storing messenger RNAs (mRNAs) away in cellular compartments called stress granules. This defence 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 they are dependent on host cell resources to produce viral proteins and replicate. Because stress granules also act as sentinels to sense viral attack, viruses have developed strategies to disable their function. Stress granules are also of increasing importance because of recent observations that they are implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease, as well as resistance to cancer chemotherapy.Caliciviruses are an important family of small viruses that can cause diseases both in humans and animals. In humans they primarily cause gastroenteritis but also cause general and respiratory infections in animals. Using animal caliciviruses, we previously made significant advances in identifying new mechanisms that viruses use to manipulate the host cell and counteract the cell's defence systems. Based on our recent results, we are now proposing that in response to virus infection, a novel mechanism allows uninfected cells to activate stress responses and prepare for viral assault. This mechanism is novel and we think it represents a new line of defence against viruses. Therefore, our objectives are to use a combination of cell biology, virology and biochemical methods to 1- characterise the composition of stress granules assembled in response to infection; understand their role in 2- the remodelling of protein synthesis and 3- the antiviral response, and 4- identify which soluble molecules stimulate this mechanism.From this work we expect to fully understand how viruses regulate the assembly of stress granules, and prime an antiviral state. We can then identify new ways to inhibit virus replication. Therefore, our work will characterise a new mechanism of antiviral response. It will advance our basic knowledge of how stress granules control gene expression and aid in the development of novel antiviral therapies for this important group of viruses, and later other viruses that control stress pathways.

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。为了应对感染等应激，细胞可以暂停蛋白质合成或翻译，从而通过将信使RNA（mRNA）储存在称为应激颗粒的细胞隔室中来解码遗传信息。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，因为它们依赖宿主细胞资源来产生病毒蛋白和复制。由于应激颗粒也可以作为感知病毒攻击的哨兵，病毒已经开发出了使其功能失效的策略。压力颗粒也越来越重要，因为最近的观察表明，它们与神经退行性疾病，如肌萎缩性侧索硬化症和阿尔茨海默病，以及对癌症化疗的抵抗有关。杯状病毒是一个重要的小病毒家族，可以引起人类和动物的疾病。在人类中，它们主要引起胃肠炎，但也引起动物的一般和呼吸道感染。利用动物杯状病毒，我们以前在确定病毒用于操纵宿主细胞和抵消细胞防御系统的新机制方面取得了重大进展。基于我们最近的研究结果，我们现在提出，在应对病毒感染时，一种新的机制允许未感染的细胞激活应激反应并为病毒攻击做好准备。这种机制是新颖的，我们认为它代表了对抗病毒的新防线。因此，我们的目标是使用细胞生物学、病毒学和生物化学方法的组合来确定响应感染而组装的应激颗粒的组成;了解它们在2-蛋白质合成的重塑和3-抗病毒反应中的作用，及4-确定哪些可溶性分子刺激这种机制。从这项工作中，我们希望充分了解病毒如何调节应激颗粒的组装，并启动抗病毒状态然后我们就可以找到抑制病毒复制的新方法。因此，我们的工作将揭示一种新的抗病毒反应机制。它将推进我们对应激颗粒如何控制基因表达的基本知识，并有助于开发针对这一重要病毒群以及随后控制应激途径的其他病毒的新型抗病毒疗法。

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

Norovirus infection results in assembly of virus-specific G3BP1 granules and evasion of eIF2a signaling

诺如病毒感染导致病毒特异性 G3BP1 颗粒组装并逃避 eIF2a 信号传导

• DOI: 10.1101/490318
• 发表时间: 2018
• 作者: Brocard M