Biomolecular condensates as organizers of mRNA decay in bacteria

生物分子凝聚体作为细菌 mRNA 衰变的组织者

• 批准号: 10594433
• 负责人: William Seth Childers
• 金额: $ 30.78万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-21 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594433
• 关键词: Alphaproteobacteria; Antibiotics; Bacteria; Bacterial Genes; Behavior; Binding; Biochemical Pathway; Biochemistry; Biological Assay; Brucella abortus; C-terminal; Cattle; Caulobacter crescentus; Cell division; Cell physiology; Cells; Chronic Granulomatous Disease; Collaborations; Crowding; Cytoplasmic Granules; Data; Development; Disease; Eukaryota; Exhibits; Exonuclease; Gene Expression Regulation; Genetic; Goals; In Vitro; Knowledge; Learning; Life; Lipids; Liquid substance; Mammalian Cell; Membrane; Messenger RNA; Organelles; Pathogenesis; Pathway interactions; Peptidoglycan; Permeability; Phase; Physical condensation; Physiological; Physiological Processes; Plants; Process; Proteins; RNA; RNA Decay; RNA Degradation; Reagent; Regulation; Rhizobium radiobacter; Ribonucleases; Ribonucleoproteins; Role; Sodium Chloride; Stress; Structure; Testing; Untranslated RNA; Virulence; Work; enzyme activity; enzyme pathway; experimental study; fitness; in vivo; inhibitor; insight; mRNA Decay; mRNA Transcript Degradation; pathogen; ribonuclease E; scaffold; self assembly; stress granule; success

Despite the absence of organelles, bacteria exhibit an intricate subcellular organization that is required for cells to grow, divide and replicate. A key question is how do simple bacteria go beyond bags of molecules to spatially and temporally organize physiological processes needed to sustain life and regulate development? It has been shown that bacteria achieve subcellular organization using microcompartments, curvature sensing, nucleoid occlusion, and unique lipid and peptidoglycan composition at the cell poles. Liquid-phase separated droplets, termed biomolecular condensates, spatially organize biochemical pathways as membraneless organelles in eukaryotes including P-bodies and stress granules. In collaboration with Jared Schrader's lab, we discovered that ribonuclease Rnase E forms liquid-phase separated bacterial ribonucleoprotein bodies (BR-bodies) that share similarities with P-bodies and stress granules. In this proposal we investigate: 1) the mechanisms that promote Rnase E BR-body formation, 2) mechanisms that regulate selective permeability of BR-bodies to messenger RNA over non-coding RNAs, and 3) the role of Rnase E scaffolding and biomolecular condensation upon mRNA decay. Our studies of BR-bodies will likely provide an illuminating initial example of biomolecular condensates as central organizers of biochemistry within bacteria, and reveal new modes of genetic regulation. This new understanding of mRNA decay should also reveal new insights into regulatory processes that govern bacterial virulence pathways and identify potential antibiotic strategies that disrupt BR-body functions.

尽管没有细胞器，细菌却表现出复杂的亚细胞组织 这是细胞生长、分裂和复制所必需的。一个关键问题是简单细菌如何 超越分子袋，在空间和时间上组织生理过程 需要维持生命和调节发展吗？研究表明，细菌能够达到 使用微区室、曲率传感、类核闭塞等进行亚细胞组织 细胞两极独特的脂质和肽聚糖成分。液相分离的液滴， 称为生物分子凝聚物，在空间上将生化途径组织为无膜 真核生物中的细胞器，包括 P 体和应激颗粒。与贾里德合作 Schrader的实验室，我们发现核糖核酸酶Rnase E形成液相分离 与 P 体和应激具有相似性的细菌核糖核蛋白体（BR 体） 颗粒。在本提案中，我们研究：1) 促进 Rnase E BR-body 的机制 形成，2) 调节 BR 体对信使 RNA 选择性渗透的机制 相对于非编码 RNA，以及 3) Rnase E 支架和生物分子缩合的作用 mRNA 衰变时。我们对 BR 体的研究可能会提供一个具有启发性的初步例子 生物分子凝聚体作为细菌内生物化学的中心组织者，并揭示了新的 遗传调控模式。对 mRNA 衰变的新认识也应该揭示新的 深入了解控制细菌毒力途径的监管过程并识别潜在的 破坏 BR 体功能的抗生素策略。