Ribosome Quality Control Mechanisms in Gram-positive Bacteria

革兰氏阳性细菌的核糖体质量控制机制

• 批准号: 10674019
• 负责人: Heather Feaga
• 金额: $ 36.69万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674019
• 关键词: Address; Antibiotic Resistance; Antibiotics; Area; Bacillus anthracis; Bacillus subtilis; Biochemical; Cell physiology; Cells; Code; Data; Event; Gene Expression; Genetic; Goals; Gram-Negative Bacteria; Gram-Positive Bacteria; Infection; Knowledge; Laboratories; Modeling; Pathway interactions; Physiological; Process; Protein Biosynthesis; Protein Truncation; Proteome; Quality Control; Regulation; Research; Ribosomes; Terminator Codon; Translational Regulation; Translations; United States; biological adaptation to stress; flexibility; interest; premature; prevent; programs

Project Summary: Although bacterial ribosomes have been biochemically interrogated for decades, unknown mechanisms of regulation and quality control are regularly uncovered and targeted with new antibiotics. Major differences in translation regulation between Gram-positive and Gram-negative bacteria have come to light in recent years. Although more than 200,000 infections per year in the United States are caused by antibiotic resistant Gram- positive bacteria, major gaps remain in our understanding of how Gram-positives perform ribosome quality control. To address these gaps, my research program will focus on two major areas. 1) We will identify and characterize strategies used by Gram-positive bacteria to detect and rescue stalled ribosomes and investigate the physiological impacts of ribosome stalling. Preliminary data from my laboratory supports a model in which ribosome stalling in Bacillus subtilis and Bacillus anthracis results in frameshifting and premature translation termination. This process is expected to result in toxic truncated proteins and trigger stress responses. We will investigate this model using genetic, structural, and biochemical approaches. 2) We will determine how ribosome flexibility and atypical translation events can be used by the cell to increase coding capacity. We are particularly interested in how frameshifting and stop codon read-through regulates gene expression and how environmental inputs control this type of regulation. We will also use unbiased high throughput genetics to uncover new mechanisms that prevent stalling and that regulate programmed frameshifting and stop codon read-through.

项目摘要： 尽管细菌核糖体已在生化上质疑数十年，但未知的机制 调节和质量控制经常被新的抗生素瞄准和靶向。主要差异 近年来，革兰氏阳性和革兰氏阴性细菌之间的翻译调节已经揭示。 尽管美国每年有超过20万多个感染是由抗生素抗生素革兰氏体引起的 阳性细菌，我们对革兰氏素质量如何执行核糖体质量的理解仍然存在主要差距 控制。为了解决这些差距，我的研究计划将重点放在两个主要领域。 1）我们将确定并 表征革兰氏阳性细菌用于检测和挽救失速核糖体并研究的策略 核糖体停滞的生理影响。我实验室的初步数据支持一个模型 枯草芽孢杆菌和炭疽芽孢杆菌的核糖体停滞 终止。预计该过程会导致有毒的截短蛋白质并触发应力反应。我们将 使用遗传，结构和生化方法研究此模型。 2）我们将确定核糖体如何 细胞可以使用灵活性和非典型翻译事件来增加编码能力。我们特别是 对框架和停止密码子如何调节基因表达以及环境如何调节如何调节密码子的感兴趣 输入控制这种类型的法规。我们还将使用公正的高吞吐量遗传学来揭示新的 防止失速并调节编程的帧和停止密码子读取的机制。