Proteome reprogramming by tRNA-cleaving toxins

项目摘要 结核分枝杆菌(Mtb)已经适应了从我们的免疫反应中存活下来的各种攻击。 到抗菌疗法--旨在根除这种微生物。然而，分子开关能够使 结核分枝杆菌能够承受这些压力，减缓复制，或者成为潜伏的结核病感染，而不是 为人所知。关于应激生存的分子基础的新研究指向毒素的活性 结核分枝杆菌毒素-抗毒素系统的组成部分，参与介导向非复制持续状态的转换 以潜伏的结核病感染为特征的。这份R21提案概述了测试该小说的实验 假设这些毒素的子集不是全局抑制翻译，而是高度特异的tRNase 这触发了核糖体移帧和核糖体停滞的组合，以外科方式操纵结核分枝杆菌 蛋白质组作为改变这种病原体的生理和/或代谢的一种手段。

Project Summary Mycobacterium tuberculosis (Mtb) has adapted to survive a wide range of assaults—from our immune response to antimicrobial therapeutics—intended to eradicate the organism. However, the molecular switches that enable Mtb to endure these stresses, to slow replication or to become dormant as a latent tuberculosis infection are not known. Emerging studies on the molecular underpinnings of stress survival point to the activity of the toxin component of Mtb toxin-antitoxin systems in mediating the switch to the non-replicating persistent state characteristic of latent tuberculosis infection. This R21 proposal outlines experiments that test the novel hypothesis that a subset of these toxins do not globally inhibit translation but instead are highly specific tRNases that trigger a combination of ribosome frameshifting and ribosome stalling to surgically manipulate the Mtb proteome as a means to alter the physiology and/or metabolism of this pathogen.