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: 10376044
• 负责人: William Seth Childers
• 金额: $ 30.82万
• 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/10376044
• 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; 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; base; 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，细菌仍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的细菌 超越了分子袋，在空间和时间上组织生理过程， 维持生命和调节发育所需的能量研究表明，细菌 使用微区室的亚细胞组织，曲率传感，类核闭塞，和 在细胞两极的独特的脂质和肽聚糖组成。液相分离液滴， 被称为生物分子凝聚物，在空间上将生物化学途径组织为无膜的 真核生物中的细胞器，包括P体和应激颗粒。与Jared合作 Schrader的实验室，我们发现核糖核酸酶E形成液相分离 细菌核糖核蛋白体（BR体）与P体和应激具有相似性 颗粒。在这个建议中，我们调查：1）促进RNase E BR体的机制， 形成，2）调节BR体对信使RNA的选择性渗透性的机制 3）RNase E支架和生物分子缩合的作用 在mRNA衰变时。我们对BR体的研究可能会提供一个有启发性的初步例子， 生物分子凝聚物作为细菌内生物化学的中心组织者，并揭示了新的 基因调控模式。这种对mRNA衰变的新理解也应该揭示新的 对控制细菌毒力途径的调控过程的深入了解， 破坏BR体功能的抗生素策略。