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Regulation of VapC toxins by Ser/Thr phosphorylation of VapB antitoxins in M. tuberculosis

结核分枝杆菌中 VapB 抗毒素的 Ser/Thr 磷酸化对 VapC 毒素的调节

基本信息

批准号：
9978276
负责人：
ROBERT N HUSSON
金额：
$ 26.55万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-21 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978276
关键词：
Address Affect Affinity Chromatography Bacteria Bacterial Physiology Bacterial Toxins Binding Biological Assay Cell physiology Cells Cleaved cell Communicable Diseases DNA Data Development Endoribonucleases Family Foundations Gene Expression Genes Genus Mycobacterium Goals Granuloma Growth Infection Investigation Knowledge Lead Messenger RNA Molecular Morbidity - disease rate Mycobacterium bovis Mycobacterium tuberculosis Operon Pathogenesis Pathway interactions Phenotype Phosphorylation Phosphorylation Site Phosphotransferases Physiology Play Promoter Regions Protein Kinase Proteins Proteome RNA Regulation Research Research Proposals Ribosomal RNA Role Signal Transduction Site Stress System Technology Testing Toxin Transfer RNA Translations Tuberculosis Two-Hybrid System Techniques Virulence Work antibiotic tolerance antimicrobial tolerance antitoxin enzyme activity human pathogen insight member mortality novel novel strategies promoter receptor response stress tolerance transcriptome sequencing

项目摘要

PROJECT SUMMARY The long-term goal of this research is to understand how Mycobacterium tuberculosis toxin-antitoxin systems are regulated to contribute to tuberculosis pathogenesis. The specific goal of this R21 research proposal is to investigate our hypothesis that Ser/Thr phosphorylation of VapB antitoxins by receptor-type Ser/Thr protein kinases represents a novel mechanism by which VapC toxins can be regulated in response to environmental signals. VapC toxins are the majority of all TA toxins in M. tuberculosis and have been implicated in proteome remodeling, growth arrest, antibiotic tolerance and ability to survive a range of stresses that are relevant for tuberculosis pathogenesis. The established role of VapB antitoxins in sequestering cognate VapC toxin proteins and autoregulating vapBC gene expression, together with our recent finding of significantly decreased phosphorylation of several VapB proteins in the setting of specific kinase depletion, provide the premises for this research. This research proposal has two Aims. In Aim 1 we will determine the effects of phosphorylation of two VapB antitoxins on i) the growth of M. tuberculosis expressing these antitoxins together with their cognate VapC toxins, and ii) the molecular interactions of these VapB toxins with their cognate VapC proteins and their cognate promoters. In Aim 2 we will investigate the effects of phosphorylation of these VapB antitoxins on VapC enzyme activity. This research will test our hypothesis that VapB Ser/Thr phosphorylation may be a means to regulate VapC activity and will begin to characterize the molecular mechanism(s) by which this regulation occurs. Results from this research will provide the foundation for further investigation into how Ser/Thr phosphorylation of VapB antitoxins can function to transduce signals to control the activity of VapC toxins that are relevant for M. tuberculosis growth control, stress tolerance and tuberculosis pathogenesis.

项目概要这项研究的长期目标是了解结核分枝杆菌毒素-抗毒素如何系统受到调节以促进结核病发病机制。 R21研究的具体目标提议是调查我们的假设，即受体类型对 VapB 抗毒素的 Ser/Thr 磷酸化 Ser/Thr 蛋白激酶代表了一种新机制，通过该机制可以调节 VapC 毒素以响应环境信号。 VapC 毒素是结核分枝杆菌中所有 TA 毒素的大部分，并且已被与蛋白质组重塑、生长停滞、抗生素耐受性和一系列应激生存能力有关与结核病发病机制相关。 VapB 抗毒素在隔离中的既定作用同源 VapC 毒素蛋白和自动调节 vapBC 基因表达，以及我们最近的发现在特定激酶耗尽的情况下，多种 VapB 蛋白的磷酸化显着降低，为本研究提供前提。这项研究计划有两个目标。在目标 1 中，我们将确定两个磷酸化的影响 VapB 抗毒素对表达这些抗毒素及其同源物的结核分枝杆菌的生长有影响 VapC 毒素，以及 ii) 这些 VapB 毒素与其同源 VapC 蛋白的分子相互作用及其同源启动子。在目标 2 中，我们将研究这些 VapB 抗毒素的磷酸化对 VapC 酶活性。这项研究将检验我们的假设，即 VapB Ser/Thr 磷酸化可能是调节的一种手段 VapC 活性并将开始表征这种调节发生的分子机制。这项研究的结果将为进一步研究 Ser/Thr 磷酸化如何提供基础 VapB 抗毒素可以转导信号来控制 VapC 毒素的活性，这些毒素与结核分枝杆菌生长控制、应激耐受性和结核病发病机制。