Mechanisms of Lipid Droplet Protein Targeting

项目概要 脂质储存是生物体缓冲可用性和需求波动的基本过程 代谢能量。脂质主要以中性脂质形式储存在细胞器中，例如三酰甘油 (TG) 称为脂滴（LD）。这些细胞器是新陈代谢的中心，具有大部分生化功能 由靶向其表面的蛋白质执行。与 LD 蛋白的重要功能一致 代谢，它们在 LD 上的异常积累可能导致疾病，例如肝病或脂肪营养不良。 尽管 LD 蛋白具有根本重要性及其与人类生理学和病理学的密切联系， 关于蛋白质如何靶向 LD 的机制知之甚少。在本提案中，我们针对一些人解决了这个问题 最初插入内质后靶向 LD 的最重要的脂质代谢酶 网状结构。利用上一个资助期的成果，我们将定义机械建造桥梁 ER 和 LD 之间的蛋白质靶向，并破译运输至 LD 的分子驱动力。 完成这些目标将揭示进化保守的细胞生物学的一个基本方面。自从 LD上蛋白质变异体的积累会导致常见的代谢疾病，我们也可能提供新的 干预的治疗途径。

PROJECT SUMMARY Lipid storage is a fundamental process for organisms to buffer fluctuations in the availability and need for metabolic energy. Lipids are predominantly stored as neutral lipids, such as triacylglycerols (TGs), in organelles called lipid droplets (LDs). These organelles are hubs of metabolism with most of their biochemical functions being executed by proteins targeting their surface. Consistent with the important function of LD proteins in metabolism, their aberrant accumulation on LDs can cause diseases, such as liver disease or lipodystrophy. Despite the fundamental importance of LD proteins and their intimate link to human physiology and pathology, little is known about the mechanisms how protein target LDs. In this proposal, we address this question for some of the most important lipid metabolism enzymes that target LDs after initial insertion into the endoplasmatic reticulum. Capitalizing on results from the previous funding period, we will define the machinery building bridges between the ER and LDs for protein targeting and decipher the molecular driving forces for transport to LDs. Completing these aims will reveal a fundamental aspect of evolutionarily conserved cell biology. Since accumulation of protein variants on LDs causes common metabolic diseases, our may also provide new therapeutic avenues for intervention.