Protein secretion in bacterial pathogens

细菌病原体的蛋白质分泌

• 批准号: 9905481
• 负责人: Oren S Rosenberg
• 金额: $ 39.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-08 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905481
• 关键词: ATP phosphohydrolase; Abscess; Bacteria; Biochemical; Biogenesis; Biological; Biological Models; Cell Wall; Cells; Cessation of life; Characteristics; Cloning; Complex; Crystallization; Cytoplasmic Tail; Data; Development; Disease; ELF3 gene; Foundations; Funding; Genetic; Genus Mycobacterium; Goals; Gram-Negative Bacteria; Gram-Positive Bacteria; Health Care Costs; Hybrids; Image; In Vitro; Infection; Infrastructure; Knowledge; Light; Mammalian Cell; Maps; Mass Spectrum Analysis; Membrane; Methods; Modeling; Monitor; Motor; Mycobacterium smegmatis; Mycobacterium tuberculosis; Pathogenicity; Peptide Signal Sequences; Pharmacologic Substance; Population; Post-Translational Regulation; Preparation; Protein Family; Protein Secretion; Proteins; Proteomics; Public Health; Regulation; Reporting; Resolution; Role; Site; Staphylococcus aureus; Statistical Data Interpretation; Structure; System; Techniques; Testing; Translating; Tuberculosis; Vaccines; Virulence; Virulence Factors; Virulent; active method; base; cell type; design; experimental study; in vivo; in vivo Model; insight; live cell imaging; mutant; mycobacterial; novel strategies; novel therapeutic intervention; particle; pathogen; pathogenic bacteria; protein expression; reconstruction; structural biology; thermophilic bacteria; tuberculosis treatment

Project Summary This project brings together structural, biochemical, proteomic and genetic expertise at UCSF to provide a detailed understanding of the structure and post-translational regulation of a key virulence factor in Mycobacterium tuberculosis. A hallmark of virulent, intracellular bacteria is their use of specialized secretion systems to inject proteins into mammalian cells. Multiple such systems are known in Gram-negative bacteria (termed the Type I-VI and VIII-IX) systems), but only one is found exclusively in Gram-positive bacteria: the type VII secretion (T7S) system. Mycobacterium tuberculosis uses multiple T7S systems to promote infection through secretion of effectors. In fact, the main genetic difference between the harmless vaccine strain BCG and pathogenic M. tuberculosis is the loss of the ESX-1 T7S system. T7S is also essential for abscess formation in Staphylococcus aureus and other pathogens may require T7S for virulence, as these systems are broadly conserved in Gram-positive bacteria. In this proposal we aim to build on our preliminary data regarding the basic mechanisms of T7S and unravel the biochemical and structural foundations of this complex biological machine.

项目概要 该项目汇集了加州大学旧金山分校的结构、生化、蛋白质组和遗传专业知识， 提供对关键毒力因子的结构和翻译后调节的详细了解 结核分枝杆菌。有毒的细胞内细菌的一个标志是它们使用专门的分泌物 将蛋白质注射到哺乳动物细胞中的系统。在革兰氏阴性细菌中已知有多个这样的系统 （称为 I-VI 型和 VIII-IX 型）系统），但仅在革兰氏阳性菌中发现一种： VII 型分泌（T7S）系统。结核分枝杆菌利用多个T7S系统促进感染 通过效应子的分泌。事实上，无害疫苗株卡介苗之间的主要基因差异 而致病性结核分枝杆菌则是 ESX-1 T7S 系统的缺失。 T7S对于脓肿也是必不可少的 金黄色葡萄球菌和其他病原体中的形成可能需要 T7S 才能发挥毒力，因为这些系统 在革兰氏阳性菌中广泛保守。在本提案中，我们的目标是基于我们的初步数据 T7S 的基本机制，并揭示这种复杂生物的生化和结构基础 机器。