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: 8070904
• 负责人: Joseph David Mougous
• 金额: $ 0.97万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-07 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8070904
• 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; 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紧密相关。遵循 许多进化上不同的途径是在致病革兰氏阴性阴性中易位的蛋白质易位 细菌（I-VI型）。第六型分泌（T6S）是这些途径的最近描述的，这是一个重要的 导致许多致病细菌的毒力的贡献者。该提案的PI，Joseph Mougous博士，首先 在铜绿假单胞菌中表征了这种分泌系统。这项工作产生了基本 对分泌系统的生化和结构见解；此外，它提供了T6S的证据 铜绿假单胞菌的系统（T6SS）对于毁灭性的慢性感染很重要 囊性纤维化患者。该提案的重点以及穆古斯博士的主要研究重点 实验室将了解紧密调节铜绿假单胞菌活性的调节途径 T6SS。这种让人联想到真核信号传导的途径是通过二聚化的 跨膜丝氨酸 - 硫代激酶。这引起了一系列“触发”分泌系统的事件， 导致底物易位。虽然莫古斯博士的先前工作揭示了一些机械 该途径的详细信息，许多关键问题仍未得到解决。拟议的实验试图回答 这些机械性问题，并利用这种新颖的监管方式，以识别 分泌系统的底物 - 当前对该领域的障碍。许多意义的病原体 人类的健康和生物形式需要T6来毒力，并使用此途径来调节其活性。所以， 拟议研究产生的发现将具有广泛的影响，并可能导致发展 新的治疗策略。