Role of very long chain fatty acids in protein quality control and membrane homeostasis

极长链脂肪酸在蛋白质质量控制和膜稳态中的作用

基本信息

批准号：
10223380
负责人：
John W Hanna
金额：
$ 35.8万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10223380
关键词：
Acyl Coenzyme A Address Area Cells Cellular biology Ceramides Coenzyme A Complex Conceptions Data Defect Development Diabetes Mellitus Diazepam Binding Inhibitor Disease Drosophila genus Endoplasmic Reticulum FAT gene Functional disorder Genes Homeostasis Insulin Resistance Lead Lecithin Ligase Lipids Malignant Neoplasms Mass Spectrum Analysis Mediating Mediator of activation protein Membrane Metabolic Neurodegenerative Disorders Obesity Parkinson Disease Pathway interactions Play Property Proteins Publishing Quality Control Role Signal Transduction Stress Structure Testing Thick Toxic effect Very Long Chain Fatty Acid Work Yeasts alpha synuclein base biological adaptation to stress desaturase fascinate fatty acid metabolism fluidity human disease insight lipid disorder lipid metabolism lipidomics loss of function luminal membrane misfolded protein mutant programs protein misfolding proteostasis response sensor synuclein

项目摘要

Project Summary/Abstract Cells have developed complex stress responses to identify and eliminate misfolded proteins. An exciting development in recent years has been the recognition that lipid homeostasis is critical for protein quality control. The Unfolded Protein Response (UPR) senses misfolded proteins in the endoplasmic reticulum and orchestrates a broad program of cellular remodeling to address this threat. Various defects in lipid metabolism trigger the UPR, and the UPR in turn controls the expression of some lipid metabolic genes. Furthermore, in contrast to the canonical luminal signaling mechanism for misfolded proteins, recent work indicates the presence of a second sensor pathway that detects defects in the ER membrane ("bilayer stress"). The functional properties of membranes (e.g. thickness, fluidity, curvature) are largely determined by their compositions. Far from early conceptions of membranes as static or inert structures, we now understand that membranes are highly dynamic and capable of altering their compositions in response to changing cellular conditions/needs. This proposal focuses on a poorly understood group of lipids known as very long chain fatty acids (VLCFAs) which are relatively unabundant but perform critical functions. We hypothesize that VLCFAs play key roles in protein quality control and membrane homeostasis. To inhibit VLCFA utilization, we have studied a mutant of the major VLCFA CoA synthetase, Fat1. Our preliminary data indicate that Fat1 plays an important role in ER homeostasis, and its loss triggers compensatory induction of the UPR. To understand the basis for this effect, we carried out a mass spectrometry-based lipidomic analysis. Remarkably, the fat1Δ mutant showed a dramatic increase in membrane saturation which is a known inducer of the UPR. This effect is mediated, at least in part, via partial loss of function of Ole1, the sole fatty acyl desaturase in yeast. In Aim 1, we will determine the mechanism by which VLCFAs regulate membrane homeostasis and the UPR. Recent data implicate membrane saturation as a key determinant of alpha-synuclein toxicity, which is responsible for Parkinson's disease. Our data indicate that Fat1 is an important regulator of synuclein toxicity. In Aim 2, we will determine mechanism by which VLCFAs regulate synuclein toxicity in yeast and Drosophila. Completion of this proposal is expected to provide both basic and disease-oriented mechanistic insight into this emerging but fundamental area of cell biology.

项目概要/摘要细胞已经产生了复杂的应激反应来识别和消除错误折叠的蛋白质。近年来的发展已经认识到脂质稳态对于蛋白质质量控制至关重要。未折叠蛋白质反应 (UPR) 感知内质网中错误折叠的蛋白质并协调为解决这一威胁而进行的广泛的细胞重塑计划引发了脂质代谢的各种缺陷。 UPR 反过来又控制一些代谢脂质基因的表达。错误折叠蛋白质的典型管腔信号传导机制，最近的工作表明存在第二个检测 ER 膜缺陷（“双层应力”）的传感器通路。膜（例如厚度、流动性、曲率）在很大程度上是由其成分决定的。膜作为静态或惰性结构的概念，我们现在了解到膜是高度动态的并能够改变其组成以响应不断变化的细胞条件/需求。重点关注一组人们知之甚少的脂质，称为极长链脂肪酸 (VLCFA)，它们相对来说我们发现 VLCFA 在蛋白质质量控制中发挥着关键作用。为了抑制 VLCFA 的利用，我们研究了主要 VLCFA CoA 的突变体。我们的初步数据表明，Fat1 在 ER 稳态及其丧失中发挥着重要作用。为了了解这种效应的基础，我们进行了大规模的研究。值得注意的是，fat1Δ突变体显示膜的显着增加。饱和是 UPR 的已知诱导剂，这种效应至少部分是通过部分功能丧失来介导的。在目标 1 中，我们将确定 VLCFA 的作用机制。调节膜稳态和 UPR 最近的数据表明膜饱和度是一个关键的决定因素。 α-突触核蛋白毒性，它是导致帕金森病的原因。我们的数据表明 Fat1 是一种。在目标 2 中，我们将确定 VLCFA 的调节机制。预计该提案的完成将为酵母和果蝇中的突触核蛋白毒性提供基础和参考。以疾病为导向的机制洞察细胞生物学这一新兴但基本的领域。