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

生物体必须对营养、温度、氧气等环境变化以及感染和激素等信号迅速作出反应。这通常是通过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。这是通过在整个细胞内发送信号来传达导致细胞内协调和广泛变化的紧急状态来实现的。这使得蛋白质的彻底改变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被称为应激颗粒的无膜细胞器，这是对应激的普遍第一线反应。生物学教科书将脂质双层膜包裹细胞器（如内质网或线粒体）定义为细胞的主要组织原理。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隔室中，它们可以加速其组分之间的反应或作为临时储存场所。应力颗粒（SGs）是无膜细胞器的一个范例，也是本研究的重点。已经为SGs提出了几个功能。首先，它们有助于分类和划分细胞介质，如核酸和蛋白质，确定哪些是适应新条件所需的，哪些是多余的。其次，它们储存的蛋白质可以发出信号，触发对压力的特定反应。第三，它们在疾病中很重要；如果SGs失调也会导致脑病、癌症和影响病毒性疾病的结果。尽管它们在人类疾病中具有明显的重要性，但关于SGs在病毒感染过程中如何发挥作用的主要问题仍然没有解决。包括我们自己的研究已经表明，SGs可以是亲和抗病毒。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成分，然而一些病毒诱导的SGs似乎有利于它们的复制。然而，关于支撑这一现象的机制的信息很少。我们已经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和新工具，我们准备阐明SGs如何介导亲病毒和抗病毒反应。我们的研究计划将综合指纹鉴定不同病毒感染细胞内形成的SGs，以确定其组成，相互作用和功能。我们将揭示SGs有助于细胞防御病毒的分子机制，并定义一些病毒如何劫持这些细胞器来促进自身复制。最终，这项工作的结果将促进我们对细胞生物学的新和基本方面的理解，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健康长寿。

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.