The Psp response of Yersinia enterocolitica

描述(申请人提供)：耶尔森氏菌属细菌导致多种人类疾病。鼠疫杆菌引起臭名昭著的疾病鼠疫，由于它可能被用作生物恐怖主义的代理人，因此在公众意识中重新引起了关注。相比之下，假结核和小肠结肠炎耶尔森菌主要引起胃肠道疾病。然而，尽管疾病症状不同，这三个致病耶尔森氏菌却密切相关，并拥有几个共同的毒力决定因素。耶尔森氏菌的研究为细菌的发病机制提供了基本的见解，包括第一个广泛存在的三型分泌系统(T3SS)的例子。所有T3SS的一个关键成分是一种特殊的外膜成孔蛋白，称为分泌素。然而，分泌素的产生会导致细菌细胞被膜应激。这对小肠结肠炎耶尔森菌是致命的，除非被称为噬菌体-休克-蛋白(PSP)系统的关键应激反应起作用。因此，小肠结肠炎耶尔森菌的PSP系统对其毒力是必不可少的。迄今为止，我们对PSP系统的研究已经确定了它的核心组成部分，并开始确定它们的作用。我们未来的工作将建立在这样的假设基础上，即小肠结肠炎耶尔森菌PSP系统的调节是由复杂和动态的蛋白质-蛋白质相互作用介导的，而激活的系统起到的作用是应对与细胞膜相关的问题，例如由错误定位的分泌素引起的问题。为了解决这些假设，我们建议：(1)测试PspFABC蛋白如何构成一个信号转导系统的各种模型，该系统如何通过蛋白质-蛋白质的动态相互作用调节PSP基因的表达；(2)分析PSPB和PSPC蛋白的调节和生理功能，它们在系统中扮演多种重要角色；(3)直接分析促胰液素毒性、促胰液素错误定位到细胞膜和PSP系统在小肠结肠炎耶尔森菌中的功能之间的关系。除了小肠结肠炎耶尔森菌外，这些研究还具有广泛的意义，因为对毒力至关重要的分泌素系统和PSP系统在医学上重要的细菌中广泛存在。因此，通过了解PSP系统，我们将进一步了解细菌对宿主感染期间发生的应激条件做出反应的基本能力。

DESCRIPTION (provided by applicant): Bacteria of the genus Yersinia are responsible for a variety of human diseases. Y. pestis causes the infamous disease Plague, which has regained prominence in public awareness due to its potential use as an agent of bioterrorism. In contrast, Y. pseudotuberculosis and Y. enterocolitica cause primarily gastrointestinal disease. However, despite the differences in disease symptoms, these three pathogenic Yersinia species are closely related, and share several common virulence determinants. Yersinia studies have provided fundamental insights into bacterial pathogenesis, including the first example of the widespread type three secretion system (T3SS). A critical component of all T3SSs is a specialized outer membrane pore-forming protein known as a secretin. However, secretin production can cause bacterial cell envelope stress. This is lethal to Y. enterocolitica unless a critical stress response known as the phage-shock-protein (Psp) system is functional. As a result, the Psp system of Y. enterocolitica is essential for its virulence. Our studies on the Psp system to date have identified its core components and begun to define their roles. We will base our future work on the hypotheses that regulation of the Y. enterocolitica Psp system is mediated by complex and dynamic protein- protein interactions, and that the activated system functions to counter problems associated with the cytoplasmic membrane, such as can be caused by a mislocalized secretin. To address these hypotheses we propose to: (1) Test various models of how the PspFABC proteins may constitute a signal transduction system that regulates psp gene expression via dynamic protein-protein interactions; (2) Analyze the regulatory and physiological functions of the PspB and PspC proteins, which play multiple essential roles in the system; (3) Directly analyze the connections between secretin toxicity, secretin mislocalization to the cytoplasmic membrane, and the function of the Psp system in Y. enterocolitica. These studies also have broad significance beyond Y. enterocolitica because secretin-containing systems critical for virulence, and the Psp system, are widespread in medically important bacteria. Therefore, by understanding the Psp system we will gain further insight into the essential ability of bacteria to respond to stressful conditions that occur during host infection.