Unlocking the secrets of specialised ribosomes across eukaryotes

基因的表达产生蛋白质是生命的基础，因此，蛋白质合成的调控至关重要。对于所有形式的生命，核糖体是负责蛋白质生产的机器。直到最近，人们还认为核糖体都是平等的，起着被动的作用，只是产生蛋白质；但新的证据表明，核糖体之间存在着许多差异，甚至在单一生物体中也是如此。这些差异现在被认为使核糖体群能够翻译特定的基因，因此在蛋白质生产中提供了一个未被探索的调节层。这些不同种类的核糖体改变了组成和目标功能，被称为“特化核糖体”，是我们项目的重点。虽然到目前为止已经确定了几种类型的专门化，但我们对专门化核糖体靶向特定mRNA库的机制知之甚少。此外，我们目前对特殊核糖体的了解主要集中在单一生物体上，而不是所有形式的生命。这是一个特别具有挑战性的问题，因为它需要各种专家方法的不同专业知识。为了解决这些问题，我们将从一组不同的生物和模型中研究专门的核糖体：酵母、昆虫、植物、人类干细胞和病毒感染期间。我们将采用双管齐下的方法：1)我们从我们的初步结果和文献中选择了5种类型的核糖体特化，我们将在所有模型系统中详细描述；2)我们将通过进化分析发现新的核糖体特化候选者。每种形式的特化将使用3种不同的方法进行探索：进化（不同生物体的共同特征是什么），翻译（这些不同的核糖体翻译什么基因）和结构（特化核糖体的结构如何实现特化）。此外，我们将开发新的工具来了解核糖体如何调节蛋白质生产，包括使用非常小的孔（纳米孔）在单个核糖体水平上研究核糖体的差异。在这个项目中产生的所有数据将被整合到一个新的公共平台中，以确保项目在拨款结束后的遗产。总的来说，我们的研究计划将确定核糖体特化的共同模式，从而揭示解释特化核糖体在生命中的行为方式的规则。考虑到了解特殊核糖体如何工作所需的方法范围，需要slola级别的资助。这些方法中的每一种都非常专业，我们的项目需要每一种方法的研究人员。此外，在单个系统中工作不会在理解方面提供重大飞跃。只有在不同的模型系统中找到共同的主题和模式，我们才能理解解释特殊核糖体如何调节蛋白质生产的规则。这个项目有可能影响对几种人类疾病的认识。具体来说，有一个由核糖体成分突变引起的疾病家族，核糖体病，我们的工作可能为疾病的机制和潜在的治疗靶点提供见解。专门的核糖体也被认为是在癌症等疾病期间产生的。这种“肿瘤核糖体”可能有助于解除对癌症中蛋白质合成的调节。我们的研究计划将导致在未来的医疗，农业和生物技术应用中调节核糖体组成和输出的新能力。总而言之，这个剖析特化核糖体调控机制的项目将使我们能够制定一个“核糖体代码”来解释整个生命中核糖体翻译调控的共同机制，并重写分子生物学核心教条的教科书。

The expression of genes to generate proteins is the foundation of life and, therefore, the regulation of protein synthesis is critical. For all forms of life, the ribosome is the machine responsible for protein production. Until recently it was thought that ribosomes were all equal and played a passive role, simply producing proteins; but new evidence suggests that many differences exist between ribosomes, even within a single organism. These differences are now thought to enable groups of ribosomes to translate specific genes, therefore providing an unexplored regulatory layer in protein production. These different kinds of ribosomes with altered composition and targeted function are termed 'specialised ribosomes', and are the focus of our project. Although a few types of specialisation have been identified so far, we know little about the mechanism by which specialised ribosomes target specific mRNA pools. Furthermore, our current understanding of specialised ribosomes is focused on single organisms, not across all forms of life. This is a particularly challenging problem to unravel because it requires diverse expertise in a variety of specialist approaches. To tackle these issues, we will study specialised ribosomes from a group of diverse organisms and models: yeast, insects, plants, human stem cells and during viral infection. We will employ a two-pronged approach: 1) we have selected 5 types of ribosome specialisations from our preliminary results and from the literature that we will characterise in detail across all our model systems; and 2) we will unearth novel candidates of ribosome specialisation through evolutionary analyses. Each form of specialisation will be explored using 3 different approaches: evolution (what are the common features in different organisms), translation (what genes these different ribosomes translate) and structural (how the structure of specialised ribosomes enables specialisation). In addition, we will develop novel tools to understand how ribosomes regulate protein production, including using very small pores (nanopores) to study differences in ribosomes at the single ribosome level. All the data generated within this project will be integrated in a novel public platform, ensuring the legacy of the project well after the end of the grant. Overall, our programme of research will identify common patterns of ribosome specialisation, and therefore unravel the rules which explain the ways in which specialised ribosomes act across life. Given the range of approaches required to understand how specialised ribosomes work, sLoLa-level funding is required. Each of these approaches is so specialised that our project requires research staff expert in each. In addition, working in individual systems would not provide a significant leap forward in understanding. Only by finding common themes and patterns across different model systems we will be able to understand the rules which explain how specialised ribosomes regulate protein production. This project has the potential to impact understanding of several human diseases. Specifically, there is a family of diseases caused by mutations of ribosome components, ribosomopathies, for which our work may provide insight into the mechanisms of disease and potential therapeutic targets. Specialised ribosomes have also been suggested to be generated during disease e.g. cancer. Such 'onco-ribosomes' might contribute to deregulating protein synthesis in cancer. Our research programme will lead to the novel ability to modulate ribosome composition and output in future medical, agricultural, and biotechnological applications. In summary this project to dissect the regulatory mechanisms of specialised ribosomes will enable us to formulate a 'ribosome code' to explain shared mechanisms of ribosome translation regulation across life and re-write the textbooks on the central dogma of molecular biology.