Molecular Mechanisms of Organelle-based Metabolic Signaling

基于细胞器的代谢信号传导的分子机制

• 批准号: 10623647
• 负责人: Roberto Zoncu
• 金额: $ 58.76万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623647
• 关键词: Cell physiology; Cells; Cellular Membrane; Cholesterol; Communication; Complex; Cyclic AMP-Dependent Protein Kinases; Cytoplasm; Dedications; Disease; Endoplasmic Reticulum; FRAP1 gene; Functional disorder; Goals; Growth; Growth Factor; Health; Homeostasis; Lipids; Lysosomes; Malignant Neoplasms; Measures; Mediating; Membrane; Metabolic; Metabolic Diseases; Molecular; Neimann-Pick' s Disease Type C; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutrient availability; Organelles; Organism; Oxygen; Pathogenicity; Pathway interactions; Phosphotransferases; Physiological; Proliferating; Protein Kinase; Regulation; Role; Signal Pathway; Signal Transduction; Site; Sterols; Surface; Time; detection of nutrient; driving force; human disease; novel therapeutic intervention; programs; recruit; response; sensor

ABSTRACT The molecular mechanisms through which cells sense nutrients remain largely unknown, but their elucidation is key to our understanding of metabolic regulation both in normal and disease states. At the center of nutrient sensing and growth regulation is an ancient protein kinase known as the mechanistic Target of Rapamycin Complex 1 (mTORC1). In response to the combined action of metabolic inputs such as nutrients, growth factors, energy and oxygen, mTORC1 translocates from the cytoplasm to the surface of lysosomes, where it becomes activated. Accumulating evidence indicates that aberrant mTORC1 activation at the lysosome could be a driving force in diseases ranging from cancer to type-2 diabetes to neurodegeneration. Thus, a deep mechanistic understanding of how mTORC1 is activated and then inactivated in response to nutrients could point the way to novel therapeutic strategies in these diseases. My lab has made important contributions to the understanding of mTORC1 pathway organization, and how its function is integrated with the many activities of the lysosome. In particular, we have identified a dedicated signaling pathway via which cholesterol, an important building block for cellular membranes, promotes mTORC1 recruitment to the lysosome and activation of its downstream programs. We have uncovered membrane contact sites between lysosomes and the endoplasmic reticulum as key nodes where mTORC1 activation by cholesterol occurs, thus implicating inter-organelle communication as an important aspect of mTORC1 regulation. Furthermore, we found that excess mTORC1 signaling, caused by cholesterol accumulation in the lysosome, drives cellular dysfunction and could be a driving force in a neurodegenerative and metabolic disease, Niemann-Pick type C (NPC). These discoveries directly lead to deep questions on the organization of cellular nutrient sensing, which are at the core of the current MIRA proposal. One key challenge is to elucidate the mechanisms and physiological roles of lipid-dependent mTORC1 regulation, specifically whether dedicated cholesterol sensors exist in the lysosomal membrane, and how they couple the abundance of sterol molecules to mTORC1 activation and to overall metabolic regulation at the cell and organism level. Based on our finding that cholesterol sensing by mTORC1 involves physical communication between the lysosome and the ER, another major goal of the proposal is to delineate the machinery that mediates communication and metabolite exchange between the lysosome and the ER, and how this machinery participates in regulation of mTORC1 as well as another major metabolic kinase, protein kinase A. Finally, the pathogenic role of dysregulated mTORC1 in NPC, and the ability of mTORC1 inhibition to restore several parameters of NPC cell function, strongly support mTORC1 as a prime target in neurodegenerative disease. We will thus determine how lysosomal mTORC1 controls neuronal cell homeostasis, and how dysregulated mTORC1 signaling contributes to neuronal degeneration. Together, these studies will shed light on fundamental principles of metabolic organization in health and disease states.

抽象的 细胞感知营养物质的分子机制仍然很大程度上未知，但它们的 阐明是我们理解正常和疾病状态下代谢调节的关键。在中心 营养感应和生长调节是一种古老的蛋白激酶，被称为机械靶标 雷帕霉素复合物 1 (mTORC1)。为了响应营养物质等代谢输入的综合作用， 生长因子、能量和氧气，mTORC1从细胞质易位到溶酶体表面， 它被激活的地方。越来越多的证据表明，溶酶体中 mTORC1 的异常激活 可能是癌症、2型糖尿病和神经退行性疾病等疾病的驱动力。于是，一个深 对 mTORC1 如何响应营养物质而被激活然后失活的机制的理解可能会指出 这些疾病的新治疗策略的方法。我的实验室为该领域做出了重要贡献 了解 mTORC1 通路组织，以及其功能如何与 mTORC1 通路的许多活动相结合 溶酶体。特别是，我们已经确定了一条专门的信号传导途径，胆固醇（一种重要的物质）通过该信号传导途径 细胞膜的构建模块，促进 mTORC1 募集至溶酶体并激活其 下游计划。我们发现了溶酶体和内质之间的膜接触位点 网织作为胆固醇激活 mTORC1 的关键节点，因此涉及细胞器间 通讯是 mTORC1 调节的一个重要方面。此外，我们发现过量的 mTORC1 由溶酶体中胆固醇积累引起的信号传导会导致细胞功能障碍，并可能是一种驱动因素 神经退行性和代谢性疾病 Niemann-Pick C 型 (NPC) 中的力量。 这些发现直接引发了关于细胞营养传感组织的深刻问题， 是当前 MIRA 提案的核心。一项关键挑战是阐明其机制和生理学 脂质依赖性 mTORC1 调节的作用，特别是专用胆固醇传感器是否存在于 溶酶体膜，以及它们如何将大量的甾醇分子与 mTORC1 激活结合起来 细胞和有机体水平的整体代谢调节。根据我们的发现，胆固醇通过 mTORC1 涉及溶酶体和 ER 之间的物理通讯，这是该药物的另一个主要目标 提议是描绘介导细胞之间沟通和代谢物交换的机制。 溶酶体和 ER，以及该机制如何参与 mTORC1 以及另一个主要的调节 最后，mTORC1 失调在 NPC 中的致病作用，以及 mTORC1 抑制可恢复 NPC 细胞功能的多个参数，强烈支持 mTORC1 作为主要药物 神经退行性疾病的目标。因此我们将确定溶酶体 mTORC1 如何控制神经元细胞 稳态，以及 mTORC1 信号传导失调如何导致神经元变性。在一起，这些 研究将揭示健康和疾病状态下代谢组织的基本原理。