Mechanisms of lipophagy, the selective autophagy of lipid droplets

项目摘要/摘要 吞脂性是脂滴的选择性自噬，是调节细胞周期的重要机制。 大多数真核细胞的细胞内脂代谢。噬脂作用是通过将LDS从 胞浆到裂解室(哺乳动物中的溶酶体或酵母中的液泡)。与其他自噬动物一样 途径，核心自噬机制形成了隔离LD的自噬隔离膜 从细胞质中分离出来。然而，这种自噬膜在诱导脂噬时是如何识别LD的 未知。此外，目前还不清楚吞脂性在其他时间是如何得到控制的。因此，吞脂性 选择性和调控是我们理解这一自噬途径的关键空白。机械论 对这些领域的了解对于准确控制人类的吞脂性是至关重要的，以预防和 治疗过多的脂肪堆积性疾病，包括脂肪肝、衰老代谢综合征、 肥胖和动脉粥样硬化。最近，我们发现了一种新的脂噬蛋白1负调控因子(Nrl1) 特异性抑制酵母中的脂噬作用，但不能抑制非选择性自噬作用。我们的初步数据表明 Nrl1的功能从酵母到哺乳动物细胞都是保守的，它促进LDS的积累 在小鼠巨噬细胞中。因为一种特定的脂噬抑制物将是治疗的好靶点 在如此多的疾病状态下上调该途径，我们研究计划的第一个项目将是 致力于调节Nrl1的吞脂性。我们将研究吞脂性的分子机制。 Nrl1的抑制作用，它对脂噬途径的特异性以及Nrl1对脂代谢的影响 细胞水平(酵母和巨噬细胞)和有机水平(斑马鱼)。我们的第二个项目 研究计划将重点放在脂噬的选择性机制上。通过追踪监管机构 Nrl1的影响，我们将确定其效应器，即特定于脂噬的选择性因子。我们还将延长 对LD蛋白质组的选择性研究，并确定可能在Nrl1- 独立时尚。对吞脂性特异性因素的全面分析是一个重要的挑战 由于这些因素定义了吞脂性途径，因此可以用来控制它，并有望 新的自噬蛋白。进化保守的吞脂因子将在两个 细胞(酵母和巨噬细胞)和有机(斑马鱼)水平。我们会产生吞脂性不足 斑马鱼模型与nrl1结构性吞脂性模型一起将构成新的有价值的工具 阐述吞脂性对各种脂质堆积性疾病的具体作用。

Project Summary/Abstract Lipophagy, the selective autophagy of lipid droplets (LDs), is an essential mechanism that regulates the intracellular lipid metabolism in most eukaryotic cells. Lipophagy is accomplished by the delivery of LDs from the cytosol to the lytic compartment (lysosome in mammals or vacuole in yeast). As in other autophagic pathways, the core autophagic machinery forms the autophagic isolation membrane that sequesters the LD from the cytosol. However, how this autophagic membrane recognizes the LD when lipophagy is induced is unknown. Also, it is not clear how lipophagy is kept in check the rest of the time. Therefore, lipophagy selectivity and regulation are the key gaps in our understanding of this autophagic pathway. The mechanistic understanding in these areas is critical for the precise control of lipophagy in humans for the prevention and treatment of a whole plethora of lipid accumulation diseases, including fatty liver, metabolic syndrome of aging, obesity and atherosclerosis. Recently, we discovered a novel negative regulator of lipophagy 1 (Nrl1) that specifically represses lipophagy but not non-selective autophagy in yeast. Our preliminary data suggest that the function of Nrl1 is conserved from yeast to mammalian cells and that it promotes the accumulation of LDs in murine macrophages. Since a specific suppressor of lipophagy would be such a good therapeutic target for upregulation of the pathway in so many disease states, the first project of our research program will be dedicated to the regulation of lipophagy by Nrl1. We will study the molecular mechanism of lipophagy repression by Nrl1, how specific it is for the lipophagy pathway and the impact of Nrl1 on lipid metabolism at both the cellular (yeast and macrophages) and organismal (zebrafish) levels. The second project of our research program will be focused on the selectivity mechanisms of lipophagy. By tracking down the regulatory effects of Nrl1, we will identify its effectors, the lipophagy-specific selectivity factors. We will also extend the selectivity studies to the LD proteome and identify the selectivity factors that might be regulated in an Nrl1- independent fashion. Comprehensive analyses of the lipophagy-specific factors is an important challenge to be addressed, since such factors define the lipophagy pathway, can be used to control it and are expected to be the new autophagic proteins. The evolutionary conserved lipophagy factors will be studied further at both the cellular (yeast and macrophages) and organismal (zebrafish) levels. We will generate lipophagy-deficient zebrafish models that together with the nrl1 model of constitutive lipophagy will constitute new valuable tools to address the specific contribution of lipophagy to various lipid accumulation diseases.