Mycobacterium bovis aconitase-IRE interactions: integrating iron, oxidative and nitrosative stress responses

牛分枝杆菌乌头酸酶-IRE相互作用：整合铁、氧化和亚硝化应激反应

• 批准号: 1688094
• 金额: --
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1688094
• 关键词: Mycobacterium; bovis; aconitase; IRE; interactions

Mycobacterium bovis is the causative agent of bovine TB, a major problem for UK cattle farming. We have identified an iron-responsive element (IRE) in the 5' coding region of an M. bovis gene, which encodes an essential cell wall hydrolase. IREs in target messenger RNA molecules are recognized by the apo-form of aconitase proteins (Acn) to mediate post-transcriptional gene expression. The regulatory function of Acn is triggered by collapse of the [4Fe-4S] cluster, which is present at the active site when Acn acts as an enzyme in the Krebs cycle, in response to the oxidative/nitrosative stress conditions that prevail in M. bovis's preferred niche - a lung macrophage. This project is based on the hypothesis that M. bovis Acn is a trigger enzyme that participates in regulatory circuits linking central metabolic function to cell wall remodeling in response to the macrophage environment.Whilst the function of eukaryotic Acns in regulation of iron homeostasis has been well-characterized, the role of bacterial Acns is understudied. Cell-wall remodeling is a fundamental feature of TB pathogenesis in the transition between replicative and non-replicative states that characterize active and latent stages of infection. Understanding the mechanism of switching between catalytic and regulatory roles of M. bovis Acn and the role this plays in shutting down central metabolism (Acn is essential for mycobacterial growth) and remodeling the cell-wall will provide the scientific underpinning to establish the significance of post-transcriptional regulation in M. bovis persistence.

牛分枝杆菌是牛结核病的病原体，而牛结核病是英国养牛业的一个主要问题。我们在牛分枝杆菌基因的 5' 编码区中鉴定了铁响应元件 (IRE)，该元件编码必需的细胞壁水解酶。靶信使 RNA 分子中的 IRE 被脱辅基形式的顺乌头酸酶蛋白 (Acn) 识别，以介导转录后基因表达。 Acn 的调节功能是由 [4Fe-4S] 簇的崩溃触发的，当 Acn 作为克雷布斯循环中的酶时，该簇存在于活性位点，响应牛分枝杆菌首选生态位（肺巨噬细胞）中普遍存在的氧化/亚硝化应激条件。该项目基于以下假设：牛分枝杆菌 Acn 是一种触发酶，参与调节回路，将中央代谢功能与响应巨噬细胞环境的细胞壁重塑联系起来。虽然真核 Acns 在调节铁稳态中的功能已得到充分表征，但细菌 Acns 的作用尚未得到充分研究。细胞壁重塑是结核病发病机制的一个基本特征，在复制和非复制状态之间的转变是感染活跃和潜伏阶段的特征。了解牛分枝杆菌 Acn 的催化和调节作用之间的转换机制及其在关闭中枢代谢（Acn 对于分枝杆菌生长至关重要）和重塑细胞壁中所发挥的作用，将为确定转录后调节在牛分枝杆菌持久性中的重要性提供科学基础。