Mechanisms of Lipid Droplet Protein Targeting

项目摘要 脂质储存是生物体缓冲可用性和需求波动的基本过程， 代谢能脂质主要以中性脂质的形式储存在细胞器中，如三酰甘油（TG 称为脂滴（LDs）。这些细胞器是代谢的枢纽，具有大部分生化功能 由蛋白质靶向其表面执行。这与LD蛋白在肿瘤中的重要功能相一致。 在代谢中，它们在LD上的异常积累可引起疾病，例如肝病或脂肪营养不良。 尽管LD蛋白具有根本的重要性，并且与人类生理学和病理学密切相关， 关于蛋白质如何靶向LD的机制知之甚少。在本提案中，我们针对一些人提出了这个问题， 最重要的脂质代谢酶的目标LD后，最初插入到内质网 网状细胞。利用上一个资助期的成果，我们将确定建造桥梁的机器 ER和LD之间的蛋白质靶向和破译分子驱动力运输到LD。 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。以来 蛋白质变体在LD上的积累导致常见的代谢疾病，我们还可以提供新的 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.