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.

活生物体必须对养分，温度，氧气以及感染和荷尔蒙等信号的环境变化迅速反应。这通常是通过在暂停和适应方法中限制饥饿的蛋白质合成过程来介导的。这是通过在整个细胞中发送信号来传达紧急状态的情况来实现的，从而导致细胞的协调和广泛变化。这允许对蛋白质进行大修，从而有利于在新条件下促进生存的蛋白质。这种适应的关键是形成了称为应力颗粒的膜细胞器，这是对压力的通用第一线反应。文本生物学定义了脂质双层膜包裹细胞器，例如内质网或线粒体，是细胞的主要组织原理。但是，识别膜细胞器为细胞生物学带来了新的范式。膜的细胞器非常适合快速适应应力，因为通过隔离特定隔室中的核酸和蛋白质可以加快其组件之间的反应或充当临时存储位点。应力颗粒（SGS）是无膜细胞器的范式，并且是该研究项目的重点。已经提出了SGS的几个功能。首先，它们有助于对细胞介质进行分类和分离，例如核酸和蛋白质，这些核酸和蛋白质定义了适应新条件和多余条件所需的细胞介质。第二，它们存储了可以发送信号以触发应激的特定反应的蛋白质。第三，它们在疾病中很重要。如果SGS的失调也可以导致大脑疾病，癌症和对病毒疾病结果的影响。尽管对人类疾病的重要性很明显，但关于SGS在病毒感染过程中的功能仍然存在的主要尚未解决的问题。包括我们本人在内的研究表明，SG可以是Pro和抗病毒。它们是对压力的普遍第一线反应，可以选择具有抗病毒活性的组件，但是一些病毒会诱导SGS似乎有益于其复制。但是，关于此基础的机制的信息很少。我们对这些关键的无膜细胞器进行了开创性的研究，并利用我们的专业知识来隔离和成像这些细胞器以及新颖的工具，我们有望阐明SGS如何介导Pro和抗病毒反应。我们的研究计划将全面地在由不同病毒感染的细胞内形成的指纹SG，以识别其成分，相互作用和功能。我们将发现SGS对病毒的细胞防御有助于的分子机制，并定义某些病毒也可以劫持这些细胞器以促进其自身的复制。最终，这项工作的结果将提高我们对细胞生物学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期健康的生活。