Coupling Gene Expression to Flagellar Morphogenesis

基因表达与鞭毛形态发生的耦合

基本信息

批准号：
7931770
负责人：
KELLY T HUGHES
金额：
$ 4.48万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7931770
关键词：
5&apos Untranslated Regions ATP phosphohydrolase Address Amino Acid Substitution Amino Acids Anabolism Animals Antibodies Area Back Bacteria Binding Biological Assay Biological Models Bion Bypass C-terminal Cell Cycle Cell membrane Cells Cessation of life Complex Coupled Couples Coupling Cytoplasm DNA Microarray Chip Development Ensure Filament Flagella Flagellin Fluorescent Probes Gene Expression Gene Expression Regulation Genes Genetic Transcription Genetic Translation Gold Green Fluorescent Proteins Growth Half-Life Individual Infection Lactamase Length Location Measures Membrane Messenger RNA Modeling Molecular Molecular Chaperones Morphogenesis N-terminal Names Nature Operon Organelles Patients Penetration Phase Plants Plasmids Play Positioning Attribute Process Protein Secretion Proteins Proteome RNA Sequences RNA-Binding Proteins RNA-Protein Interaction Regulation Reporter Reporting Research Role Salmonella Sampling Septicemia Signal Transduction Specificity Staging Structure Substrate Specificity System Testing Time Transcript Translating Translations Trematoda Type III Secretion System Pathway Typhoid Fever Untranslated Regions Vaccines Variant Virulence Work base fliC gene product follow-up gene repression genetic regulatory protein in vivo inhibitor/antagonist interest kinetosome mutant pathogen periplasm polymerization premature prevent promoter retinal rods vaccine development yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Salmonella pathogens infect over a billion people each year worldwide resulting in 3 million deaths annually from septicemia, mostly in HIV-infected patients and 700,000 from typhoid fever (W.H.O. estimates). It is one of many gram-negative plant and animal pathogens that have evolved specialized secretion systems, Type III Secretion (TTS) Systems, to facilitate the ordered delivery of virulence effector proteins. The pathogenic TTS systems evolved from the flagellar system, and ensures the efficient, ordered assembly of the bacterial flagellum. The virulence systems have maintained the ordered delivery mechanism of the TTS apparatus to ensure that individual virulence determinants are secreted at the appropriate stage of the infection process. The flagellum serves as a model TTS system for understanding how regulatory mechanisms control the assembly of large structures, and how the TTSS can differentially select substrates for secretion at the appropriate stage of the infection process. We are studying the mechanisms that coordinate the regulation of flagellar gene expression to the assembly of the bacterial flagellum. We have previously shown that one critical regulatory mechanism involves a switch in the secretion substrate specificity of the flagellar TTS apparatus upon hook-basal body (HBB) completion. The secretion of late substrates releases bound secretion chaperones, sigma 28, FlgN, and FliT to initiate gene regulation at the time of HBB completion (checkpoint!). We will determine what targets specific proteins for secretion at their proper assembly time. Specific mechanisms to be investigated include the nature of the flagellar TTS signal, the secretion specificity switch that controls flagellar hook length and the switch in secretion specificity from hook-type substrates to late secretion substrates. We have strong evidence that the FliK protein acts as a molecular ruler to control the final length of the rod-hook complex, and rod-length control is intrinsic to the rod protein FlgG. We will continue to investigate the dual roles for Type III Secretion Chaperones (TTSC) in assembly and gene regulation and in the process of localized translation of secretion substrates at the cytoplasmic base of the flagellum. We will determine the role of the membrane-anchored regulator, Flk, which senses outer membrane penetration and prevents premature secretion of late substrates prior to HBB completion. Because the TTS system is a target for vaccine development against gram-negative pathogens, understanding the process of assembly, secretion and regulation of the flagellar model system will aid in the development of such vaccines.

描述（由申请人提供）：每年在全球范围内有十亿人的沙门氏菌病原体感染了数十亿人，每年导致300万人因败血病而死亡，大部分患有HIV感染的患者，而伤寒患者700,000人（W.H.O.估计）。它是许多革兰氏阴性型动植物病原体之一，它们已经进化了专门的分泌系统，即III型分泌（TTS）系统，可促进毒力效应蛋白的有序递送。致病性TTS系统从鞭毛系统演变，并确保细菌鞭毛的有效组装有序。毒力系统维护了TTS设备的有序递送机制，以确保在感染过程的适当阶段分泌单个毒力决定因素。鞭毛是一种模型TTS系统，用于了解调节机制如何控制大型结构的组装，以及TTSS如何在感染过程的适当阶段在适当的阶段分泌分泌的底物。我们正在研究协调鞭毛基因表达与细菌鞭毛组装的调节的机制。我们先前已经表明，一种关键的调节机制涉及钩 - 巴萨体（HBB）完成后鞭毛TTS设备的分泌底物特异性转换。晚期底物的分泌释放了绑定的分泌伴侣，Sigma 28，Flgn和FliT在HBB完成时启动基因调节（检查点！）。我们将在适当的装配时间内确定哪些针对特定蛋白质的蛋白质。要研究的特定机制包括鞭毛TTS信号的性质，控制鞭毛钩长度的分泌特异性开关以及从钩型基板到晚分泌底物的分泌特异性。我们有强有力的证据表明，FLIK蛋白充当分子尺来控制杆钩复合物的最终长度，并且杆长度对照对杆蛋白FLGG是固有的。我们将继续研究组装和基因调节中III型分泌伴侣（TTSC）的双重作用，以及在鞭毛的细胞质碱基的分泌底物的局部翻译过程中。我们将确定膜锚定调节剂FLK的作用，该调节剂FLK感应外膜穿透并防止HBB完成之前的后期底物的过早分泌。由于TTS系统是针对革兰氏阴性病原体开发疫苗的目标，因此了解鞭毛模型系统的组装，分泌和调节过程将有助于开发此类疫苗。