Friends or foes: dissecting the crosstalk between stress granules and viruses during infection

朋友还是敌人：剖析感染过程中应激颗粒和病毒之间的串扰

• 批准号: BB/W015536/2
• 负责人: Nicolas Locker
• 金额: $ 49.13万
• 依托单位: The Pirbright Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW015536%2F2
• 关键词: Friends; foes; dissecting; crosstalk; between

Living organisms must respond rapidly to environmental changes in nutrients, temperature, oxygen and also to infection and signals such as hormones. This is frequently mediated by limiting the energy hungry process of protein synthesis in a pause and adapt approach. This is achieved by sending signals throughout the cell to communicate a state of emergency leading to coordinated and widespread changes in the cell. This allows for an overhaul of proteins to favour proteins that facilitate survival under the new conditions. A key to this adaptation is the formation of membraneless organelles called stress granules which are a universal first line response to stress.Textbook biology defines lipid bilayer membrane wrapping organelles, such as the endoplasmic reticulum or mitochondria, as the main organising principle of a cell. However, the identification of membraneless organelles presents a new paradigm for cell biology. Membraneless organelles are perfectly suited to rapid adaptation to stress as by sequestering nucleic acids and proteins in specific compartments they can speed up reactions between their components or act as temporary storage sites. Stress granules (SGs) are a paradigm for membraneless organelles and the focus of this research project.Several functions have been proposed for SGs. First, they help sort and compartmentalize cellular mediator such as nucleic acids and proteins defining those needed to adapt to the new conditions and those which are superfluous.Second, they store proteins that can send signals to trigger specific responses to the stress. Third, they are important in diseases; if dysregulated SGs can also contribute to diseases of the brain, cancer and impact on the outcome of viral diseases. Despite their evident importance in human disease, major unsolved questions remain about how SGs function during viral infections. Research including our own has shown that SGs can be both pro and anti- viral. They are a universal first line response to stress, and can select components with antiviral activities, yet some viruses induce SGs that appear to benefit their replication. However, there is little information about the mechanisms underpinning this. We have pioneered studies into these critical membraneless organelles and using our expertise in isolating and imaging these organelles, and novel tools, we are poised to elucidate how SGs mediate pro and anti-viral responses. Our research program will comprehensively fingerprint SGs formed within cells infected by different viruses to identify their components, interactions, and functions. We will uncover the molecular mechanisms by which SGs contribute to cellular defences against viruses and define how some viruses can also hijack these organelles to promote their own replication. Ultimately, the outcome of this work will advance our understanding of novel and fundamental aspects of cell biology and importantly relate this to pathological conditions and therefore this work will contribute to long and healthy living.

生物体必须对营养物质、温度、氧气等环境变化以及感染和激素等信号做出快速反应。这通常是通过以暂停和适应方法限制蛋白质合成的能量消耗过程来介导的。这是通过在整个小区内发送信号来传达紧急状态，从而导致小区内协调和广泛的变化来实现的。这允许对蛋白质进行彻底改造，以有利于促进新条件下生存的蛋白质。这种适应的关键是形成称为应激颗粒的无膜细胞器，它们是对应激的普遍一线反应。教科书生物学将脂质双层膜包裹的细胞器（例如内质网或线粒体）定义为细胞的主要组织原则。然而，无膜细胞器的鉴定为细胞生物学提供了一个新的范式。无膜细胞器非常适合快速适应压力，因为通过将核酸和蛋白质隔离在特定的区室中，它们可以加速其成分之间的反应或充当临时储存位点。应激颗粒（SG）是无膜细胞器的范例，也是本研究项目的重点。人们已经提出了 SG 的多种功能。首先，它们帮助分类和划分细胞介质，例如核酸和蛋白质，定义适应新条件所需的物质和多余的物质。其次，它们储存可以发送信号以触发对压力的特定反应的蛋白质。第三，它们对疾病很重要；如果 SG 失调，还会导致脑部疾病、癌症，并影响病毒性疾病的结果。尽管SGs在人类疾病中具有明显的重要性，但关于SGs在病毒感染期间如何发挥作用的主要未解决问题仍然存在。包括我们自己在内的研究表明，SG 既可以促病毒，也可以抗病毒。它们是对压力的普遍一线反应，并且可以选择具有抗病毒活性的成分，但一些病毒诱导的 SG 似乎有利于它们的复制。然而，关于支撑这一机制的信息很少。我们率先研究了这些关键的无膜细胞器，并利用我们在分离和成像这些细胞器方面的专业知识以及新颖的工具，我们准备阐明 SG 如何介导亲病毒和抗病毒反应。我们的研究计划将全面对被不同病毒感染的细胞内形成的 SG 进行指纹识别，以识别它们的成分、相互作用和功能。我们将揭示 SG 有助于细胞防御病毒的分子机制，并定义某些病毒如何劫持这些细胞器以促进自身复制。最终，这项工作的成果将增进我们对细胞生物学的新颖和基本方面的理解，并重要地将其与病理条件联系起来，因此这项工作将有助于长寿和健康的生活。