Post-translational regulation of type VI secretion in Pseudomonas aeruginosa

铜绿假单胞菌 VI 型分泌的翻译后调控

• 批准号: 8277283
• 负责人: Joseph David Mougous
• 金额: $ 36.16万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-17 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277283
• 关键词: Affect; Bacteria; Biochemical; Chronic; Cues; Data; Development; Dimerization; Disease; Elements; Engineering; Enzymes; Event; Extracellular Protein; Genes; Gram-Negative Bacteria; Growth; Health; Hereditary Disease; Human; Individual; Infection; Investigation; Laboratories; Lead; Link; Lung; Maps; Microbial Biofilms; Modeling; Molecular; Morbidity - disease rate; Nature; Organism; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Post-Translational Regulation; Process; Protein Secretion; Protein translocation; Protein-Serine-Threonine Kinases; Proteins; Pseudomonas aeruginosa; Regulation; Regulatory Element; Regulatory Pathway; Research; Rest; Role; Series; Signal Transduction; Sputum; Structural Models; System; Transducers; United States; Virulence; Work; abstracting; biodefense; cystic fibrosis patients; insight; mortality; novel; novel therapeutics; pathogen; pathogenic bacteria; protein protein interaction; release factor; research study

Project Abstract The virulence of a bacterium is closely linked to its ability to release secreted factors. It follows that many evolutionarily distinct pathways exist for the translocation of proteins in pathogenic Gram-negative bacteria (types I-VI). Type VI secretion (T6S), the most recently described of these pathways, is an important contributor to the virulence of many pathogenic bacteria. The PI of this proposal, Dr. Joseph Mougous, first characterized this secretion system in Pseudomonas aeruginosa. This work produced fundamental biochemical and structural insights into the secretion system; furthermore, it provided evidence that the T6S system (T6SS) of P. aeruginosa is important for the devastating chronic infections this organism causes in cystic fibrosis patients. The focus of this proposal, and the major research emphasis of Dr. Mougous' laboratory, is to understand the regulatory pathway that tightly modulates the activity of the P. aeruginosa T6SS. This pathway, which is reminiscent of eukaryotic signaling, is initiated by dimerization of a transmembrane serine-threonine kinase. This provokes a series of events that "triggers" the secretion system, leading to substrate translocation. Although prior work by Dr. Mougous has revealed some of the mechanistic details of this pathway, many key questions remain unanswered. The proposed experiments seek to answer these mechanistic questions, and also to utilize this novel mode of regulation for the purpose of identifying substrates of the secretion system - a current impediment to the field. Many pathogens of significance to human health and biodefense require T6S for virulence and use this pathway to regulate its activity; therefore, findings generated by the proposed research will have broad implications and could lead to the development of new therapeutic strategies.

项目摘要 细菌的毒力与其释放分泌因子的能力密切相关。由此可见 致病性革兰氏阴性菌中蛋白质的易位存在许多进化上不同的途径 细菌（I-VI 型）。 VI 型分泌 (T6S) 是这些途径中最近描述的一个重要途径 导致许多病原菌的毒力。该提案的 PI 博士 Joseph Mougous 首先 表征了铜绿假单胞菌的这种分泌系统。这项工作产生了基础 对分泌系统的生化和结构见解；此外，它还提供了 T6S 的证据 铜绿假单胞菌系统（T6SS）对于该生物体引起的破坏性慢性感染非常重要 囊性纤维化患者。本提案的重点以及 Mougous 博士的主要研究重点 实验室的目的是了解严格调节铜绿假单胞菌活性的调控途径 T6SS。该途径让人想起真核信号传导，是由a的二聚化启动的 跨膜丝氨酸-苏氨酸激酶。这引发了一系列“触发”分泌系统的事件， 导致底物易位。尽管 Mougous 博士之前的工作已经揭示了一些机制 尽管关于这条路径的细节，许多关键问题仍未得到解答。拟议的实验试图回答 这些机械问题，并利用这种新颖的监管模式来识别 分泌系统的底物 - 目前该领域的障碍。许多病原体对 人类健康和生物防御需要 T6S 来发挥毒力，并利用该途径来调节其活性；所以， 拟议研究产生的结果将产生广泛的影响，并可能导致开发 新的治疗策略。