Prions in the bacterial domain of life

细菌生命域中的朊病毒

• 批准号: 10573151
• 负责人: Ann Hochschild
• 金额: $ 45.29万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573151
• 关键词: Address; Amyloid; Bacteria; Behavior; Biological Assay; Biology; Cell Death; Cell Survival; Cells; Collaborations; Development; Disease; Epigenetic Process; Escherichia coli; Event; Foundations; Genetic; Genome; Goals; Health; Heredity; Heritability; Heterogeneity; Human; Immune Evasion; Infection; Learning; Life; Mammals; Methodology; Methods; Modeling; Molecular Conformation; Neurodegenerative Disorders; Pathogenicity; Phenotype; Physiological; PrP; Prion Diseases; Prions; Property; Proteins; Proteome; Research; Role; Saccharomycetales; Source; Stress; Structural Biologist; Time; Work; Yeasts; antibiotic tolerance; bacterial fitness; conformational conversion; fungus; genetic element; human microbiota; insight; non-genetic; prion-like; programs; protein aggregation; screening; tool

ABSTRACT Prions are infectious, self-propagating protein aggregates that were first described in the context of the transmissible spongiform encephalopathies (TSEs), a group of fatal neurodegenerative diseases that afflict humans and other mammals. The culprit in the case of the TSEs is an endogenous protein called PrP that has an inherent ability to undergo a dramatic conformational conversion, leading to the formation of distinctive cross-b aggregates (termed amyloid) that are both self-templating and infectious. Prions have also been uncovered in budding yeast and other fungi, where they act as protein-based genetic elements that confer new heritable phenotypes on those cells that harbor them. Like PrP, fungal prion proteins can access alternative conformational states, a soluble form and a self-perpetuating, amyloid form (the prion form) that is infectious. Unlike PrP-based prions, however, fungal prions do not typically cause cell death; they can, in fact, enhance cell survival under specific stress conditions. The foundation for the proposed studies is our discovery that prion proteins also exist in bacteria. Our research goals are to investigate the scope of prion-like phenomena in bacteria and to probe the physiologic significance of prions in bacteria. An overarching hypothesis informing our work is that protein-based heredity can serve as an epigenetic source of phenotypic diversity in the bacterial domain of life. As well as using E. coli cells as a model in which to study prion proteins from diverse bacteria, we are extending our studies to encompass species that naturally contain prion proteins, including constituents of the human microbiota. A major methodological focus of our long-term research program has been the development of broadly applicable genetic assays, and our work here includes the development and implementation of bacteria-based genetic assays that can detect prion conversion events. These genetic tools will enable screening for prion protein encoded in bacterial (and other) genomes, facilitating the discovery of new prion proteins and potentially also new classes of prion proteins. At the same time, our tools provide facile methods for addressing mechanistic questions about prion formation and prion propagation. Our approach to understanding prion biology is multi-faceted, encompassing ongoing collaboration with structural biologists and biophysicists. Because prion proteins in all domains of life share fundamental properties, what we learn in bacteria could provide mechanistic insight relevant to prion proteins in other settings; furthermore, our bacteria- based tools can be used to investigate the behavior of bacterial and non-bacterial prion proteins alike. Bacterial prions could have far-reaching human health implications; for example, as a source of non-genetic phenotypic heterogeneity, prions might enhance bacterial fitness in a pathogenic context. Moreover, the presence of prions in the human microbiota could potentially impact human health via cross-Kingdom templating interactions involving disease-associated human proteins.

摘要 朊病毒是感染性的、自我繁殖的蛋白质聚集体， 传染性海绵状脑病（TSE）是一组致命的神经退行性疾病， 人类和其他哺乳动物。TSE的罪魁祸首是一种叫做PrP的内源性蛋白质， 一种固有的能力，经历了戏剧性的构象转换，导致形成独特的 交叉B聚集体（称为淀粉样蛋白），其既是自模板又是感染性的。朊病毒也被 在芽殖酵母和其他真菌中发现，它们作为基于蛋白质的遗传元件， 这些细胞上的遗传表型像PrP一样，真菌朊病毒蛋白可以获得替代的 构象状态，可溶性形式和具有感染性的自我永存的淀粉样蛋白形式（朊病毒形式）。 然而，与基于PrP的朊病毒不同，真菌朊病毒通常不会导致细胞死亡;事实上，它们可以增强细胞的免疫功能。 细胞在特定应激条件下的存活。这些研究的基础是我们的发现， 朊病毒蛋白也存在于细菌中。我们的研究目标是调查朊病毒样现象的范围， 探讨朊病毒在细菌中的生理意义。一个总体假设， 我们的工作是基于蛋白质的遗传可以作为表型多样性的表观遗传来源 生命的细菌领域。以及使用E.大肠杆菌细胞作为研究朊病毒蛋白的模型， 细菌，我们正在扩大我们的研究，包括自然含有朊病毒蛋白的物种，包括 人体微生物群的组成部分。我们长期研究计划的一个主要方法重点是 我们一直在开发广泛适用的基因检测，我们在这里的工作包括开发和 实施可以检测朊病毒转化事件的基于细菌的遗传测定。这些基因工具 将能够筛选细菌（和其他）基因组中编码的朊病毒蛋白，促进发现 新的朊病毒蛋白和潜在的新类型的朊病毒蛋白。与此同时，我们的工具提供了简便的 解决有关朊病毒形成和朊病毒传播的机制问题的方法。我们的方法来 理解朊病毒生物学是多方面的，包括与结构生物学家的持续合作， 生物药理学家因为朊病毒蛋白在生命的所有领域都有着共同的基本特性，我们在研究中所了解到的是， 细菌可以提供与其他环境中朊病毒蛋白相关的机制见解;此外，我们的细菌- 基于的工具可用于研究细菌和非细菌朊病毒蛋白的行为。 细菌朊病毒可能对人类健康产生深远的影响;例如，作为非遗传性疾病的来源， 表型异质性，朊病毒可能会增强细菌的适应性在致病性的情况下。而且 人类微生物群中朊病毒的存在可能会通过跨王国影响人类健康。 涉及疾病相关人类蛋白质的模板相互作用。