Lipid sensing through G protein geranylgeranylation

项目总结/摘要 脂质信号在生物体生理和代谢消耗的调节中起着关键作用。 脂质体内平衡的不平衡会对健康产生不利影响，生物体内的细胞会严格调节 脂肪的吸收、合成和代谢，以适应能量需求并确保能量储备 在以后的生活中细胞通过SREBP调节的代谢资源储存能量储备 脂肪生成然而，不太清楚的是，细胞如何调节脂质稳态下营养耗尽的条件下， 特别是，细胞如何感知代谢需求并通过增加营养吸收做出反应。我们的审核工作 C.线虫已经鉴定了一种高度反应性的小G蛋白，RAB-11.2， 其在类异戊二烯/甲羟戊酸合成途径缺陷时被转录激活。通过 进一步研究，我们发现了一种新的机制， 核激素受体，NHR-49，通过RAB-11.2进行营养吸收。 通过拟议的五年研究期，我们的目标是确定细胞感知的分子机制。 并对它们重新合成脂质的需要做出反应。我们的初步数据表明，细胞感觉到它们的 通过监测特定异戊烯醇脂质的可用性来分解脂质的能力， 类异戊二烯途径，香叶基香叶基焦磷酸。在高稳态脂质水平的条件下， RAB-11.1的牛儿基牛儿基化使其能够结合并螯合NHR-49至胞质转运囊泡， 转录不活跃状态。在由饥饿或脂肪分解缺陷/β- 氧化，细胞缺乏通过类异戊二烯途径合成GGPP的资源，这阻止了RAB- 11.1从结合囊泡和破坏营养吸收所需的内吞循环途径。由于 由于其RAB-11.1结合配偶体不能与囊泡结合，NHR-49从胞质囊泡中释放， 转移到细胞核，在那里它激活几种代谢酶，营养转运蛋白的转录 和RAB-11.2来重建营养吸收。

Project Summary/Abstract Lipid signaling plays a critical role in the regulation of organismal physiology and metabolic expenditure. Imbalances in lipid homeostasis can deleteriously impact health and cells within the organism tightly regulate lipid absorption, synthesis and metabolism to accommodate energetic demands and ensure energetic reserves later in life. Cells stockpile energy reserves under ample metabolic resources through SREBP-regulated lipogenesis. Yet, less clear is how cells regulate lipid homeostasis under nutrient depleted conditions and in particular, how cells sense metabolic demand and respond by increasing nutrient absorption. Our examination of several lipid depletion paradigms in C. elegans has identified a highly responsive small G protein, RAB-11.2, which is transcriptionally activated upon defects in the isoprenoid/mevalonate synthesis pathway. Through further investigation, we have discovered a new mechanism linking the nucleocytoplasmic dynamics of the nuclear hormone receptor, NHR-49, with nutrient absorption through RAB-11.2. Through the proposed five-year research period, we aim to define the molecular mechanism by which cells sense and respond to their need for de novo lipid synthesis. Our preliminary data suggests that cells sense their capacity to breakdown lipids through monitoring the availability of a particular prenol lipid synthesized through the isoprenoid pathway, geranylgeranyl pyrophosphate. Under conditions of high homeostatic lipid levels, geranylgeranylation of RAB-11.1 enables it to bind and sequester NHR-49 to cytosolic transport vesicles in a transcriptionally inactive state. Under lipid limited conditions caused by starvation or defective lipolysis/β- oxidation, cells lack the resources to synthesize GGPP through the isoprenoid pathway, which prevents RAB- 11.1 from binding vesicles and disrupts endocytic recycling pathways required for nutrient absorption. Due to the inability of its RAB-11.1 binding partner to associate with vesicles, NHR-49 is release from cytosolic vesicles and translocates to the nucleus where it activates transcription of several metabolic enzymes, nutrient transporters and RAB-11.2 to re-establish nutrient absorption.