PXA domain-containing proteins in lysosome function and lipid metabolism

派：W.Mike Henne，博士。 项目摘要/摘要 溶酶体是主要细胞分解代谢途径的末端细胞器，包括 自噬和内膜贩运，但令人惊讶的是，人们对它们如何去除知之甚少 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储存病(LSD)，没有普遍性 他们的治疗方法是可用的。除了它们在分解代谢中的作用外， 溶酶体也向细胞的其他细胞器提供基本代谢物，如脂肪酸(FAs)，但 管理这种机构间贩运的机制也仍然不清楚。我最近 确定了一系列蛋白质的特征，这些蛋白质可能使这种细胞器间的脂质流动成为可能。全 同源基因的特征是一种特征不佳的PX相关基因(PXA)，这是来自我的初步数据 实验室指示直接与FA绑定。我假设PXA结构域对非囊泡有贡献 细胞器间的脂质交换。有趣的是，我发现酵母中含有PXA结构域 Mdm1蛋白作为细胞器间的“系绳”，将溶酶体/液泡紧密地连接到 内质网，主要的脂肪合成细胞器。MDM1‘S苍蝇同源基因--称为 Snazurus(SNZ)-也与脂肪代谢和衰老有关，SNZ缺陷的果蝇表现出 肥胖和超长寿命。人类同源基因Snx14最近被发现与 儿童神经系统疾病，可能是由一种新发现的LSD引起的。 总而言之，我认为含有PXA结构域的蛋白质是 细胞器间的脂质流动和代谢，并可能起到促进运动的作用。 像FAs这样的代谢物在细胞器之间。因此，这些蛋白质以前就构成了 脂代谢和溶酶体内平衡的“中枢”尚未被认识，但却很重要。这项研究 这里概述的计划将定义溶酶体中含有PXA结构域的蛋白的功能 功能和脂质代谢通过三种广泛的途径：高通量基因 有机体脂质组学的筛选、细胞器间连接的重建及发展 技术。通过在我的新实验室实施这些方法，我们将建立在 范式转换时代的前沿，它将定义 非囊泡性脂类转运。这些发现有望为LSD提供新的治疗方法，以及 糖尿病和心脏病等慢性代谢综合征的新治疗策略。

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.