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Dissecting the means by which type 3 substrates are defined & secreted

剖析 3 类底物的定义方式

基本信息

批准号：
10328544
负责人：
CAMMIE LESSER
金额：
$ 51.04万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10328544
关键词：
ATP phosphohydrolase Address Binding Biochemical Biological Assay Biological Models Cells Complex Cytosol Data Development Disease Engineering Escherichia Escherichia coli Family Genetic Goals Human Infection Lead Mammalian Cell Mediating Membrane Modeling Molecular Molecular Chaperones Multi-Drug Resistance Mutagenesis N-terminal Nature Pathogenicity Pathway interactions Phylogenetic Analysis Physiological Play Process Protein Secretion Proteins Proton-Motive Force Pseudomonas aeruginosa Publishing RNA Ribosomes Role Salmonella Salmonella enterica Shigella Shigella flexneri Solid Sorting - Cell Movement Technology Translations Type III Secretion System Pathway Variant Virulence Yersinia antimicrobial antimicrobial drug base crosslink experimental study follow-up genetic approach high throughput screening in vivo insight nanomachine novel pathogen pathogenic bacteria recruit resistant strain ribosome profiling targeted agent

项目摘要

The virulence of many human bacterial pathogens is dependent on transkingdom nanomachines, including type III secretion systems (T3SSs), which act to directly deliver tens of virulence proteins, often referred to as effectors, into the cytosol of mammalian cells. Many critical gaps exist in our understanding of how type III secreted (T3S) proteins, referred to as effectors, are defined and delivered to the T3S apparatus (T3SA). While each pathogen injects its own unique set of effectors into hosts, components of their machines share a high degree of similarity. For several decades, the dogma has been that the effector secretion is dependent on small acidic T3S chaperones that bind to their N-terminal regions. These chaperones control the hierarchy of secretion of proteins by mediating their recruitment to the sorting platform, a complex that cycles between the cytosol and membrane-embedded T3SA. Interestingly, cognate chaperones have not yet been identified for the majority of T3S effectors, including those from intensively studied Salmonella, Yersinia, Shigella and pathogenic Escherichia T3SSs. Here, we present data that support the existence of a noncanonical T3SS chaperone-independent (CI) pathway likely conserved across numerous phylogenetically distinct T3SS families. Here, using the Shigella flexneri T3SS as a model system, we propose to: 1. Determine how T3S chaperones are recruited to the sorting platform. Using the Protein Interaction 2. Dissect the molecular mechanisms by which CI effectors are recognized and delivered to the T3SA. 3. Investigate the existence of a co-translational ATPase-independent type III secretion pathway. Together the proposed studies shown not only advance our understanding regarding how T3S effectors are defined and delivered to the T3SA, but also result in the identification of targets for the development of novel antimicrobial agents that target the virulence of the large family of Gram-negative bacterial pathogens whose virulence is dependent on a functional T3SS.

许多人类细菌病原体的毒力依赖于跨界纳米机器，包括