Lipid sensing through G protein geranylgeranylation

通过 G 蛋白香叶基香叶基化进行脂质传感

基本信息

批准号：
10617820
负责人：
Peter Mahan Douglas
金额：
$ 34.26万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10617820
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 Endosomes Ensure Enzymes Event Expenditure GTP-Binding Proteins Genetic Transcription Goals Hand Health Homeostasis Investigation Laboratories Life Ligands Link Lipids Lipolysis Liposomes Malabsorption Syndromes Maps Metabolic Metabolism Modeling Molecular Monitor Monomeric GTP-Binding Proteins Mutagenesis Mutation Nature Nuclear Nuclear Hormone Receptors Nuclear Receptors Nutrient Nutrient Depletion Nutritional Requirements 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 experimental study geranylgeranyl pyrophosphate geranylgeranylation isoprenoid lipid biosynthesis mevalonate mutant novel nutrient absorption oxidation paralogous gene particle prenol prenylation prevent protein degradation protein geranylgeranyltransferase response screening vesicle transport

项目摘要

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.

项目概要/摘要脂质信号传导在生物生理学和代谢消耗的调节中发挥着关键作用。脂质稳态失衡会对健康和生物体内受到严格调控的细胞产生有害影响脂质吸收、合成和代谢以满足能量需求并确保能量储备在生命后期，细胞通过 SREBP 调节，在充足的代谢资源下储存能量储备。然而，尚不清楚细胞如何在营养耗尽的条件下调节脂质稳态。特别是，细胞如何感知代谢需求并通过增加营养吸收来做出反应。线虫中的几种脂质消耗范例已经鉴定出一种高度响应的小 G 蛋白，RAB-11.2，它在类异戊二烯/甲羟戊酸合成途径缺陷时被转录激活。进一步研究，我们发现了一种连接核细胞质动力学的新机制核激素受体 NHR-49，通过 RAB-11.2 吸收营养。通过拟议的五年研究期，我们的目标是确定细胞感知的分子机制并响应它们对脂质从头合成的需要。我们的初步数据表明细胞感知它们的存在。通过监测合成的特定异戊烯醇脂质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脂质水平的条件下， RAB-11.1 的香叶基香叶基化使其能够将 NHR-49 结合并隔离在胞质转运囊泡中在饥饿或脂肪分解缺陷/β-引起的脂质限制条件下。氧化时，细胞缺乏通过类异戊二烯途径合成 GGPP 的资源，从而阻止了 RAB- 11.1 结合囊泡并破坏营养吸收所需的内吞循环途径。由于其 RAB-11.1 结合配偶体无法与囊泡结合，NHR-49 从胞质囊泡中释放出来，易位到细胞核，在那里激活多种代谢酶、营养转运蛋白的转录和 RAB-11.2 来重新建立营养吸收。