Modulation of Agr system by ClpC chaperone in S. aureus

金黄色葡萄球菌中 ClpC 伴侣对 Agr 系统的调节

基本信息

批准号：
10593669
负责人：
Chia Y. Lee
金额：
$ 19.13万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593669
关键词：
Affect Animals Bacteria Biochemical Biological Assay Cell Density Cell surface Chimeric Proteins Complex DNA Binding Data Disease Enabling Factors Environment Foundations Gene Expression Regulation Genes Genetic Transcription Genus staphylococcus Goals Gram-Positive Bacteria Homeostasis Human Immune system Infection Interferometry Knowledge Laboratories Life Maps Membrane Proteins Methods Modeling Molecular Chaperones Operon Organism Pathogenesis Pathogenicity Pathway interactions Peptide Hydrolases Peptides Pheromone Play Polysaccharides Process Production Promoter Regions Proteins Quality Control RNAIII Regulation Regulatory Pathway Regulon Reporter Research Role Small RNA Solid Staphylococcal Infections Staphylococcus aureus Surface System Technology Testing Toxin Virulence Virulence Factors Virulent capsule experimental study extracellular genetic approach human pathogen human tissue in vivo insight negative affect novel oxidation pathogen protein folding quorum sensing sensor virtual virulence gene

项目摘要

PROJECT SUMMARY The long-term goal of our research is to understand virulence gene regulation in Staphylococcus aureus. S. aureus is an important human pathogen capable of causing a wide spectrum of infections in human and animals. The pathogenicity of this organism is dependent on various virulence factors produced during infection that are controlled by a large number of regulators. Elucidation of virulence regulation by this complex regulatory network is central to understanding pathogenesis of this pathogen. However, despite extensive efforts, our knowledge of virulence regulation is still very limited. We have previously identified ClpC as part of the regulatory network capable of regulating the transcription of a large number of genes, including virulence genes. ClpC is a protein chaperone involved in protein quality control, which does not have a DNA-binding motif. We therefore hypothesize that ClpC interacts with transcriptional regulators to affect gene transcription. Indeed, our recent results provided the initial evidence to support this hypothesis. One of the regulators we identified that could interact with ClpC is AgrA, a transcriptional regulator of the AgrAC two-component system, which is part of the Agr quorum sensing system in S. aureus. The Agr quorum sensing system also includes AgrB and AgrD that are involved in pheromone AIP (auto-inducing peptide) production needed for Agr autoactivation at high cell density. Agr has been shown to be a key regulator that affects the expression of many virulence genes. Our preliminary data showed that ClpC could activate the Agr system by directly interacting with AgrA as well as by positively affecting AIP production independent of AgrA autoactivation, suggesting that ClpC could affect Agr regulatory system at two different pathways. Accordingly, in this application, we propose two specific aims to study the potential mechanisms involved in this regulation. In the first aim, we will investigate how ClpC modulates AgrA regulatory activity. In the second aim, we will study how ClpC affects AIP production. ClpC has been shown to negatively affect regulators by partnering with ClpP protease. However, how ClpC can positively modulate a regulatory system is virtually unknown. Our studies proposed in this application will not only probe the potential novel mechanisms involved in gene regulation but will also advance our understanding virulence regulation in S. aureus.

项目概要我们研究的长期目标是了解金黄色葡萄球菌的毒力基因调控。金黄色葡萄球菌是一种重要的人类病原体，能够在人类和人类中引起广泛的感染。动物。该微生物的致病性取决于感染过程中产生的各种毒力因子受到大量监管机构的控制。阐明这种复杂监管的毒力监管网络对于了解这种病原体的发病机制至关重要。然而，尽管我们付出了巨大的努力，对毒力调控的了解仍然非常有限。我们之前已将 ClpC 确定为监管的一部分网络能够调节大量基因的转录，包括毒力基因。 ClpC 是参与蛋白质质量控制的蛋白质伴侣，不具有 DNA 结合基序。我们因此假设 ClpC 与转录调节因子相互作用以影响基因转录。确实，我们最近结果提供了支持这一假设的初步证据。我们发现的监管机构之一可能与 ClpC 相互作用的是 AgrA，它是 AgrAC 双组分系统的转录调节因子，是 AgrAC 双组分系统的一部分金黄色葡萄球菌中的 Agr 群体感应系统。 Agr群体感应系统还包括AgrB和AgrD，参与高细胞 Agr 自激活所需的信息素 AIP（自诱导肽）的产生密度。 Agr 已被证明是影响许多毒力基因表达的关键调节因子。我们的初步数据表明，ClpC 可以通过直接与 AgrA 相互作用以及通过独立于 AgrA 自动激活对 AIP 产生产生积极影响，表明 ClpC 可能影响 Agr 两条不同途径的监管体系。因此，在本申请中，我们提出了两个具体目标研究这种调节所涉及的潜在机制。在第一个目标中，我们将研究 ClpC 如何调节 AgrA 调节活性。在第二个目标中，我们将研究 ClpC 如何影响 AIP 的生产。 ClpC 有已被证明通过与 ClpP 蛋白酶合作对调节剂产生负面影响。然而，ClpC 如何能够积极地调节监管系统几乎是未知的。我们在本申请中提出的研究不仅将探讨涉及基因调控的潜在新机制，也将增进我们对毒力的理解金黄色葡萄球菌中的调节。