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.

项目摘要/摘要脂质信号在调节有机生理和代谢支出中起着至关重要的作用。脂质稳态失衡会有害影响生物体内的健康和细胞。脂质抽象，合成和代谢，以适应能量需求并确保能量储量后来生活。通过SREBP调节脂肪生成。然而，尚不清楚的是细胞如何调节营养耗尽条件下的脂质稳态和特别是，细胞如何通过增加营养滥用的滥用量来感知代谢需求并做出反应。我们的检查秀丽隐杆线虫中的几种脂质耗竭范式中，已经确定了高度响应的小G蛋白Rab-11.2，在类异戊二烯/甲龙酸酯合成途径中的缺陷上被转录激活。通过进一步研究，我们发现了一种新的机制，将核眼质动力学联系起来 NHR-49的核骑马受体，通过RAB-11.2进行营养滥用。在拟议的五年研究期间，我们旨在定义细胞感知的分子机制并应对他们对从头脂质合成的需求。我们的初步数据表明细胞感知他们通过监测通过监测通过类异戊二烯途径，黄烷基焦磷酸盐。在高稳态脂质水平的条件下， Rab-11.1的香烷基凝聚力使其能够结合并隔离NHR-49与A中的胞质转运蔬菜转录状态。在脂质有限的条件下，饥饿或脂解/β-引起的条件氧化，细胞缺乏通过异急道途径合成GGPP的资源，从而阻止了Rab- 11.1从结合蔬菜和破坏营养滥用所需的内吞回收途径。由于 NHR-49无法与蔬菜结合的RAB-11.1结合伴侣，从细胞溶液和易位到核激活几种代谢酶的转录，营养转运蛋白和RAB-11.2重新建立营养滥用。