Lipid sensing through G protein geranylgeranylation

通过 G 蛋白香叶基香叶基化进行脂质传感

• 批准号: 10417568
• 负责人: Peter Mahan Douglas
• 金额: $ 33.59万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10417568
• 关键词: AGFG1 gene; Age; Aging; Alleles; Amino Acids; Apical; Binding; Biological Assay; Caenorhabditis elegans; Cell Nucleus; Cell surface; Cells; Cessation of life; Complement; Data; Defect; Ensure; Enzymes; Event; Expenditure; GTP-Binding Proteins; Genetic Transcription; Goals; Hand; Health; Homeostasis; Investigation; Laboratories; Life; Ligands; Link; Lipids; Lipolysis; Liposomes; Malabsorption Syndromes; Metabolic; Metabolism; Modeling; Molecular; Monitor; Monomeric GTP-Binding Proteins; Mutagenesis; Mutation; Nature; Nuclear; Nuclear Hormone Receptors; Nuclear Receptors; Nutrient; Organism; Pathway interactions; Phenotype; Physiological; Physiology; Play; Process; Protein Geranylgeranylation; Recycling; Regulation; Research; Residencies; Resistance; Resources; Role; Signal Transduction; Signaling Protein; Starvation; Stress; Supplementation; Testing; Time; Transcriptional Activation; Transferase; Variant; Vesicle; Work; absorption; base; experimental study; geranylgeranyl pyrophosphate; geranylgeranylation; isoprenoid; lipid biosynthesis; mevalonate; mutant; novel; nutrient absorption; oxidation; paralogous gene; particle; prenol; prevent; protein degradation; protein geranylgeranyltransferase; response; screening; vesicle transport

Project Summary/Abstract Lipid signaling plays a critical role in the regulation of organismal physiology and metabolic expenditure. Imbalances in lipid homeostasis can deleteriously impact health and cells within the organism tightly regulate lipid absorption, synthesis and metabolism to accommodate energetic demands and ensure energetic reserves later in life. Cells stockpile energy reserves under ample metabolic resources through SREBP-regulated lipogenesis. Yet, less clear is how cells regulate lipid homeostasis under nutrient depleted conditions and in particular, how cells sense metabolic demand and respond by increasing nutrient absorption. Our examination of several lipid depletion paradigms in C. elegans has identified a highly responsive small G protein, RAB-11.2, which is transcriptionally activated upon defects in the isoprenoid/mevalonate synthesis pathway. Through further investigation, we have discovered a new mechanism linking the nucleocytoplasmic dynamics of the nuclear hormone receptor, NHR-49, with nutrient absorption through RAB-11.2. Through the proposed five-year research period, we aim to define the molecular mechanism by which cells sense and respond to their need for de novo lipid synthesis. Our preliminary data suggests that cells sense their capacity to breakdown lipids through monitoring the availability of a particular prenol lipid synthesized through the isoprenoid pathway, geranylgeranyl pyrophosphate. Under conditions of high homeostatic lipid levels, geranylgeranylation of RAB-11.1 enables it to bind and sequester NHR-49 to cytosolic transport vesicles in a transcriptionally inactive state. Under lipid limited conditions caused by starvation or defective lipolysis/β- oxidation, cells lack the resources to synthesize GGPP through the isoprenoid pathway, which prevents RAB- 11.1 from binding vesicles and disrupts endocytic recycling pathways required for nutrient absorption. Due to the inability of its RAB-11.1 binding partner to associate with vesicles, NHR-49 is release from cytosolic vesicles and translocates to the nucleus where it activates transcription of several metabolic enzymes, nutrient transporters and RAB-11.2 to re-establish nutrient absorption.

项目摘要/摘要 脂质信号在调节机体生理和代谢支出方面起着至关重要的作用。 脂质平衡的失衡会有害地影响健康，机体内的细胞会受到严格的调节 脂肪的吸收、合成和代谢，以适应能量需求，确保能量储备 在以后的生活中。细胞通过SREBP调节在充足的代谢资源下储存能量储备 脂肪生成作用。然而，不太清楚的是，细胞如何在营养耗竭的条件下和在 特别是，细胞如何感知新陈代谢需求并通过增加营养吸收来做出反应。我们的考试 在线虫体内的几种脂质耗竭范例中，已经确定了一种高度响应的小G蛋白RAB-11.2， 该基因在类异戊二烯/甲氧戊酸合成途径缺陷时被转录激活。穿过 进一步的研究，我们发现了一种新的机制，将核质动力学联系在一起 核激素受体NHR-49与RAB-11.2的营养吸收有关。 通过建议的五年研究期，我们的目标是定义细胞感知的分子机制 并响应他们对从头合成脂肪的需求。我们的初步数据表明，细胞感觉到它们的 通过监测合成的特定戊烯醇脂的可用性来分解脂质的能力 类异戊二烯途径，香叶基香叶基焦磷酸。在高稳态血脂水平的情况下， RAB-11.1的香叶酰化使其能够结合和隔离NHR-49与胞浆运输囊泡。 转录不活跃状态。在饥饿或脂解缺陷/β引起的脂质限制条件下- 氧化，细胞缺乏通过类异戊二烯途径合成GGPP的资源，这阻止了RAB- 11.1结合小泡并扰乱营养吸收所需的内吞循环途径。由于 由于其RAB-11.1结合伙伴不能与囊泡结合，NHR-49从胞浆囊泡中释放出来，并 转位到细胞核，在那里它激活了几种代谢酶、营养转运蛋白的转录 和RAB-11.2来重建营养吸收。