Prions in the bacterial domain of life

摘要 Prion是具有感染性的、自我繁殖的蛋白质聚集体，最初是在 传播性海绵状脑病(TSE)是一组致命的神经退行性疾病， 人类和其他哺乳动物。在TSE的情况下，罪魁祸首是一种名为PrP的内源性蛋白质，它具有 一种固有的能力，经历戏剧性的构象转换，导致形成独特的 具有自我模板性和感染性的交叉b聚集体(称为淀粉样蛋白)。普里恩也一直被 发现在萌芽酵母和其他真菌中，它们作为基于蛋白质的遗传元素，赋予新的 携带它们的细胞上的可遗传表型。像PrP一样，真菌蛋白可以获得替代蛋白 构象状态，一种可溶的形式和一种自我延续的，具有传染性的淀粉样蛋白形式(蛋白形式)。 然而，与基于PrP的普恩不同，真菌普恩通常不会导致细胞死亡；事实上，它们可以增强 细胞在特定的应激条件下存活。拟议研究的基础是我们的发现 普恩蛋白也存在于细菌中。我们的研究目标是研究类普里子现象的范围 并探讨细菌中普恩的生理学意义。一个重要的假设告诉我们 我们的工作是，基于蛋白质的遗传可以作为表观遗传来源的表型多样性在 生命中的细菌领域。以及使用大肠杆菌细胞作为模型来研究来自不同种类的 细菌，我们正在扩大我们的研究范围，以涵盖自然含有普恩蛋白的物种，包括 人类微生物区系的组成。我们长期研究计划的一个主要方法重点是 一直在开发广泛适用的遗传分析方法，我们在这里的工作包括开发和 实施基于细菌的基因测试，可以检测到普恩转换事件。这些遗传工具 将能够筛选在细菌(和其他)基因组中编码的普恩蛋白，促进发现 新的普恩蛋白和潜在的新类别的普恩蛋白。同时，我们的工具提供了便捷的 解决有关Pron形成和Pron传播的机制问题的方法。我们的方法是 对Pron生物学的理解是多方面的，包括与结构生物学家和 生物物理学家。因为在生命的所有领域中的Prion蛋白质都有共同的基本属性，我们在 细菌可以在其他环境中提供与Pron蛋白质相关的机械洞察力；此外，我们的细菌- 基于工具的研究可以用来研究细菌和非细菌普恩蛋白的行为。 细菌蛋白可能对人类健康有深远的影响；例如，作为非遗传性的来源 表型的异质性，可能会增强细菌在致病环境中的适合性。此外， 人类微生物区系中普恩的存在可能会通过跨王国影响人类健康 模板化涉及与疾病相关的人类蛋白质的相互作用。

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.