Modulation of Agr system by ClpC chaperone in S. aureus

项目总结 我们研究的长期目标是了解金黄色葡萄球菌毒力基因的调控。 金黄色葡萄球菌是一种重要的人类病原体，能够在人类和 动物。这种微生物的致病力取决于感染过程中产生的各种毒力因子。 由大量监管机构控制的公司。通过这种复杂的调控阐明毒力调控 网络是了解这种病原体发病机制的核心。然而，尽管做出了广泛的努力，我们的 关于毒力调控的知识仍然非常有限。我们之前已将ClpC确定为监管部门的一部分 能够调控大量基因转录的网络，包括毒力基因。ClpC是一种 蛋白质伴侣参与蛋白质质量控制，它没有DNA结合基序。因此，我们 假设ClpC与转录调控因子相互作用影响基因转录。事实上，我们最近 结果提供了支持这一假设的初步证据。我们确定的监管机构之一可能 与ClpC相互作用的是AGRA，它是AGAC双组分系统的转录调控因子，是 金黄色葡萄球菌的AGR群体感应系统。AGR群体感应系统还包括农业B和农业D 参与了高级细胞中AGR自激活所需的信息素AIP(自动诱导肽)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 初步数据显示，ClpC可以通过与AGRA直接相互作用以及通过 正向影响AIP的产生，不依赖于AGRA的自激活，表明ClpC可能影响AGR 监管体系在两条不同的路径上。因此，在本申请中，我们提出了两个具体目标 研究这一监管涉及的潜在机制。在第一个目标中，我们将调查ClpC如何 调节AGRA的调节活动。在第二个目标中，我们将研究ClpC对AIP生产的影响。ClpC有 已被证明通过与ClpP蛋白酶合作对调节器产生负面影响。然而，ClpC如何积极地 调整一个监管体系几乎是未知的。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 金黄色葡萄球菌的监管。

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.