Modulation of Bacterial Cell Division by (p)ppGpp

(p)ppGpp 对细菌细胞分裂的调节

基本信息

  • 批准号:
    10315737
  • 负责人:
  • 金额:
    $ 6.6万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-08-01 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT In bacteria, cell size positively correlates with nutrient availability and negatively correlates with levels of the key nutritional signaling molecules pppGpp and ppGpp (abbreviated (p)ppGpp). (p)ppGpp is produced in response to environmental nutrient limitation and functions primarily to inhibit biosynthesis and slow growth. In the model organism Escherichia coli, (p)ppGpp modulates cell physiology at both the transcriptional and post- transcriptional levels through interactions with RNA polymerase (RNAP) and 56 additional cellular targets. However, the mechanism by which (p)ppGpp contributes to regulation of cell size is not fully understood. The balance between cell division and elongation is a major determinant of size in rod-shaped bacteria. Several pieces of evidence suggest that (p)ppGpp contributes to cell size in part by modulating the balance between these two processes. Increases in (p)ppGpp levels suppress the heat sensitivity of conditional cell division mutants and leads to resistance to mecillinam, an antibiotic targeting the elongation machinery (elongasome). These data suggest that (p)ppGpp positively affects activity of the cell division machinery (divisome). Strains lacking (p)ppGpp ((p)ppGpp0) are ~30% longer than wild-type cells and frequently filament. These phenotypes are not recapitulated in RNAP mutants defective for (p)ppGpp binding, suggesting that (p)ppGpp contributes to cell size through a post-transcriptional interaction with one of its other binding partners. I hypothesize that (p)ppGpp indirectly promotes divisome assembly and activation via interaction with its target proteins. To illuminate the molecular basis of (p)ppGpp mediated changes in divisome and elongasome activity, I propose two complementary aims. In Aim 1, I will characterize the effects of alterations in intracellular (p)ppGpp concentration on production, assembly, and activation of the cell division machinery. In Aim 2, I will screen for (p)ppGpp binding proteins that are required to increase cell length. I will then determine the effect of these proteins on the transcription, translation, assembly, and activity of divisome components (Sub-aim 2b) and, in Sub-aim 2c, determine the mechanism by which candidate proteins modulate cell division. The expected contribution of the proposed work is an enhanced understanding of the mechanisms by which (p)ppGpp modulates bacterial physiology. This contribution is significant because (p)ppGpp is a key component of environmental adaptation throughout the bacterial kingdom. This proposal will also enhance our understanding of (p)ppGpp’s role in intrinsic resistance to the clinically important β-lactam antibiotics, which target components of the divisome and elongasome. In addition, this F32 fellowship will provide me with opportunities to learn new techniques in microscopy and biochemistry, explore new conceptual avenues, and obtain additional professional training that will prepare me for a career as a professor and independent investigator.
项目摘要/摘要 在细菌中,细胞尺寸与营养可用性正相关,并且与水平负相关 关键的营养信号分子PPPGPP和PPGPP(缩写(P)PPGPP)。 (P)PPGPP在 对环境营养限制和功能的反应主要是为了抑制生物合成和缓慢的生长。在 模型生物体大肠杆菌(P)PPGPP调节转录和后的细胞生理 通过与RNA聚合酶(RNAP)相互作用和56个其他细胞靶标的转录水平。 但是,(P)PPGPP有助于调节细胞大小的机制尚不完全了解。这 细胞分裂和伸长之间的平衡是棒状细菌大小的主要确定。一些 证据表明,(p)ppGPP通过调节之间的平衡有助于细胞大小 这两个过程。 (P)PPGPP水平的增加抑制了条件细胞分裂的热敏感性 突变体并导致对靶向伸长机械的抗生素(伸长剂)的抗药性。 这些数据表明(p)PPGPP对细胞分裂机制(Divisome)的活性产生积极影响。菌株 缺乏(P)PPGPP((P)PPGPP0)比野生型细胞长30%,并且经常丝。这些表型 在(P)PPGPP结合的RNAP突变体中不概括,这表明(P)PPGPP有助于 通过与其他结合伙伴之一的转录后相互作用通过细胞大小。 我假设(p)ppgpp间接促进了除法的组件和激活 靶蛋白。阐明(P)PPGPP的分子基础介导的分裂体和伸长术的变化 活动,我提出了两个完整的目标。在AIM 1中,我将表征细胞内改变的影响 (p)PPGPP浓度在细胞分裂机械的生产,组装和激活上。在AIM 2中,我会 筛选(P)PPGPP结合蛋白,这些蛋白需要增加细胞长度。然后,我将确定 这些蛋白质在转录,翻译,组装和活性的蛋白质(sub-aim 2b) 并且,在Sub-Aim 2C中,确定候选蛋白调节细胞分裂的机制。预期 提议的工作的贡献是对(p)ppgpp的机制的增强理解 调节细菌生理学。此贡献很重要,因为(p)ppgpp是关键组成部分 整个细菌王国的环境适应。该建议还将增强我们的理解 (P)PPGPP在对临床上重要的β-内酰胺抗生素的内在耐药性中的作用,该抗生素靶向成分 divisome和Elongasome。此外,F32奖学金将为我提供新的学习机会 显微镜和生物化学方面的技术,探索新的概念途径,并获得其他专业 培训将使我成为教授和独立调查员的职业。

项目成果

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Sarah Emily Anderson其他文献

Sarah Emily Anderson的其他文献

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{{ truncateString('Sarah Emily Anderson', 18)}}的其他基金

Modulation of Bacterial Cell Division by (p)ppGpp
(p)ppGpp 对细菌细胞分裂的调节
  • 批准号:
    10458524
  • 财政年份:
    2021
  • 资助金额:
    $ 6.6万
  • 项目类别:
Modulation of Bacterial Cell Division by (p)ppGpp
(p)ppGpp 对细菌细胞分裂的调节
  • 批准号:
    10668410
  • 财政年份:
    2021
  • 资助金额:
    $ 6.6万
  • 项目类别:

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