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

• 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
• 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

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.

项目摘要 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。 S.金黄色葡萄球菌是一种重要的人类病原体，能够在人类中引起广泛的感染， 动物该菌的致病性依赖于感染过程中产生的各种毒力因子 由大量的监管机构控制。阐明毒力调节，这种复杂的调控 网络是理解这种病原体发病机制的核心。然而，尽管作出了广泛的努力， 对毒力调控的认识仍然非常有限。我们以前已经确定ClpC是监管的一部分， 该网络能够调节大量基因的转录，包括毒力基因。ClpC是一个 蛋白质伴侣参与蛋白质质量控制，其不具有DNA结合基序。因此我们 假设ClpC与转录调节因子相互作用以影响基因转录。事实上，我们最近 结果提供了支持这一假设的初步证据。我们发现的一个监管机构， 与ClpC相互作用的是AgrA，它是AgrAC双组分系统的转录调节因子， Agr群体感应系统。金黄色。Agr群体感应系统还包括Agr B和Agr D， 参与Agr在高细胞水平下自动激活所需的信息素AIP（自动诱导肽）的产生 密度的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 初步数据表明，ClpC可以通过直接与Agr A相互作用以及通过与Agr A相互作用激活Agr系统。 独立于AgrA自激活，对AIP的产生产生有积极影响，表明ClpC可以影响Agr 在两个不同的途径调节系统。因此，在本申请中，我们提出两个具体目标， 研究这种调节的潜在机制。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的产生。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如何积极地 调节调节系统实际上是未知的。我们在本申请中提出的研究不仅将探索 潜在的新机制涉及基因调控，但也将促进我们对毒力的理解 在S.金黄色。