PXA domain-containing proteins in lysosome function and lipid metabolism

含 PXA 结构域的蛋白质在溶酶体功能和脂质代谢中的作用

• 批准号: 9750013
• 负责人: Mike Henne
• 金额: $ 40.5万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750013
• 关键词: Aging; Autophagocytosis; Binding; Cells; Childhood; Chronic; Data; Defect; Diabetes Mellitus; Disease; Doctor of Philosophy; Drosophila genus; Endoplasmic Reticulum; Exhibits; Fatty Acids; Genetic Diseases; Genetic Screening; Heart Diseases; Homeostasis; Homologous Gene; Human; Lead; Lipids; Longevity; Lysosomal Storage Diseases; Lysosomes; Mediator of activation protein; Metabolic syndrome; Metabolism; Movement; Obesity; Organelles; Pathway interactions; Play; Protein Family; Proteins; Research; Role; Technology; Vacuole; Yeasts; fly; lipid metabolism; lipid transport; nervous system disorder; novel therapeutic intervention; novel therapeutics; programs; protein function; reconstitution; trafficking

PI: W. Mike Henne, Ph.D. Project Summary/Abstract Lysosomes are the terminal organelle for major cellular catabolic pathways including autophagy and endomembrane trafficking, yet remarkably little is understood about how they rid themselves of the cellular debris they generate. Defects in this efflux contribute to nearly fifty genetic diseases collectively known as lysosomal storage diseases (LSDs), and no universal therapies are available for their treatment. Beyond their roles in catabolic metabolism, lysosomes also supply basic metabolites like fatty acids (FAs) to other organelles of the cell, but the mechanisms that govern this inter-organelle trafficking also remain obscure. I recently characterized a family of proteins that potentially enable this inter-organelle lipid flux. All homologs feature a poorly characterized PX-Associated (PXA), which preliminary data from my lab indicates directly binds to FAs. I hypothesize that PXA domains contribute to non-vesicular inter-organelle lipid exchange. Interestingly, I discovered that the yeast PXA domain-containing protein Mdm1 functions as inter-organelle “tether” closely connecting the lysosome/vacuole to the Endoplasmic Reticulum, the major lipid synthesis organelle. Mdm1's fly homolog—called Snazurus (Snz)—is also implicated in lipid metabolism and aging, and snz-deficient flies exhibit obesity and hyper-extended lifespan. The human homolog Snx14 was recently implicated in pediatric neurological disease, likely caused by a newly recognized LSD. Collectively, I propose that PXA domain-containing proteins are important mediators of inter-organelle lipid flux and metabolism, and may function to promote the movement of metabolites like FAs between cellular organelles. These proteins thus constitute previously unrecognized but important “hubs” of lipid metabolism and lysosome homeostasis. The research program outlined here will define the functions of PXA domain-containing proteins in lysosome function and lipid metabolism through three broad approaches: high-throughput genetic screening, the reconstitution of inter-organelle tethering, and developing in organismo lipidomics technologies. By implementing these approaches in my new lab, we will establish ourselves on the leading edge of a paradigm-shifting era that will define new pathways and mechanisms of non-vesicular lipid trafficking. These discoveries promise new therapies for LSDs, as well as new therapeutic strategies for chronic metabolic syndromes like diabetes and heart disease.

PI：W. Mike Henne博士 项目总结/摘要 溶酶体是主要细胞分解代谢途径的终末细胞器，包括 自噬和内膜运输，但很少有人知道他们如何摆脱 它们产生的细胞碎片。这种外流的缺陷导致了近50 遗传性疾病统称为溶酶体贮积病（LSD），没有普遍的 治疗方法可用于其治疗。除了在分解代谢中的作用， 溶酶体还向细胞的其他细胞器提供基本代谢物，如脂肪酸（FAs），但 控制这种细胞器间贩运的机制也仍然不清楚。我最近 表征了可能使这种细胞器间脂质流动的蛋白质家族。所有 同源物的特点是一个不好的特点PX相关（PXA），从我的初步数据， 实验室检测表明直接与脂肪酸结合。我假设PXA结构域有助于非囊泡性 细胞器间脂质交换。有趣的是，我发现含有PXA结构域的酵母 Mdm 1蛋白作为细胞器间“系链”紧密连接溶酶体/液泡， 内质网，主要的脂质合成细胞器。mdm 1的苍蝇同系物 Snazurus（Snz）-也与脂质代谢和衰老有关，snz缺乏的果蝇表现出 肥胖和过度延长的寿命。人类同源基因Snx 14最近被认为与 小儿神经系统疾病，可能是由一种新发现的迷幻药引起的。 总的来说，我认为含有PXA结构域的蛋白质是重要的介体， 细胞器间的脂质流动和代谢，并可能起到促进运动的作用， 细胞器之间的代谢物如脂肪酸。因此，这些蛋白质以前构成 未被认识但重要的脂质代谢和溶酶体稳态的“枢纽”。研究 本文概述的一个程序将定义溶酶体中含PXA结构域蛋白的功能 功能和脂质代谢通过三个广泛的方法：高通量遗传 筛选、细胞器间连接的重建和生物脂质组学的发展 技术.通过在我的新实验室实施这些方法，我们将建立自己的 一个范式转变时代的前沿，将定义新的途径和机制， 非囊泡脂质运输。这些发现为LSD提供了新的治疗方法， 糖尿病和心脏病等慢性代谢综合征的新治疗策略。