Proteome reprogramming by tRNA-cleaving toxins

项目摘要 结核分枝杆菌（Mtb）已经适应了广泛的攻击，从我们的免疫反应中幸存下来 抗菌治疗剂-旨在根除有机体。然而，分子开关， 结核病不能忍受这些压力，减缓复制或成为潜伏性结核病感染的休眠状态 知道的关于应激生存的分子基础的新兴研究指出了毒素的活性 Mtb毒素-抗毒素系统的一个组成部分，介导向非复制持久状态的转换 潜伏性结核感染的特征。这个R21提案概述了测试小说的实验 假设这些毒素的一个子集不全面抑制翻译，而是高度特异性的tRNase 引发核糖体移码和核糖体停滞的组合，以外科手术方式操纵结核分枝杆菌 蛋白质组作为改变该病原体的生理学和/或代谢的手段。

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.