The Roles of the Dynamin-Related Protein Vps1 and the ESCRT Complex in Microautophagy

动力相关蛋白 Vps1 和 ESCRT 复合物在微自噬中的作用

• 批准号: 9354500
• 负责人: Marijn Gerard Johannes Ford
• 金额: $ 29.2万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9354500
• 关键词: Address; Antifungal Agents; Antineoplastic Agents; Autophagocytosis; Biochemical; Biology; Biophysics; Cell Survival; Cell physiology; Cells; Cellular Membrane; Cellular biology; Complex; Cytokinesis; Cytology; Data; Defect; Development; Disease; Dynamin; Embryonic Development; Eukaryota; Eukaryotic Cell; Genetic; Goals; Growth; Growth and Development function; Health; Homeostasis; Human; Length; Light; Link; Lipid Binding; Longevity; Malignant Neoplasms; Mammalian Cell; Maps; Membrane; Mission; Mitochondria; Modeling; Molecular; Multivesicular Body; Neurodegenerative Disorders; Nutrient; Organelles; Pathologic; Pathology; Pathway interactions; Play; Post-Translational Protein Processing; Process; Property; Protein Family; Proteins; Proteomics; Reaction; Recovery; Recruitment Activity; Regulation; Role; Signal Pathway; Signal Transduction; Sirolimus; Site; Speed; Stress; Structure; United States National Institutes of Health; Vacuolar Protein Sorting; Viral; Work; Yeasts; base; cell growth; fascinate; fungus; genetic approach; high resolution imaging; human disease; insight; interdisciplinary approach; member; novel; novel therapeutics; self assembly; tomography; trafficking; treatment strategy; uptake

Microautophagy is a poorly-characterized autophagic pathway defined by direct invagination of vacuolar (fungi) or lysosomal (higher eukaryotes) membrane for engulfment and degradation of organelles and cytosolic components. Microautophagy is required for cell survival under conditions of stress, such as nutrient limitation, and for resumption of cell growth on recovery from stress. Strikingly, microautophagy is also a key regulator of TOR signaling, which plays well-established roles in growth, survival and lifespan control. The molecular mechanism of microautophagy and how it regulates TOR signaling is not understood. Our long-term goal is to understand the mechanism of microautophagy and how microautophagy is harnessed to regulate signaling cascades required for growth and development. Our preliminary data demonstrates that the membrane remodeling required for microautophagy depends on the dynamin-related protein (DRP) Vps1 and the ESCRTIII component Snf7. DRPs and ESCRTs are fascinating membrane remodeling machines that are vital for several fundamental cellular processes including membrane trafficking, mitochondrial dynamics, cytokinesis and viral budding. DRPs and ESCRTs both couple membrane deformation to self-assembly. Deficiencies in DRPs and ESCRTs are associated with numerous pathologies due to their central roles in homeostasis, including neurodegenerative disorders. Our central hypothesis is that the functional interaction between DRPs and ESCRTs forms the molecular basis for membrane invagination in microautophagy. Furthermore, we propose that nutrient and stress signaling pathways converge on Vps1 and ESCRT to regulate their novel function in microautophagy to, ultimately, control TOR signaling and cell growth. Using genetic, proteomic, cytological and structural approaches, we will characterize the mechanism of recruitment of DRP and ESCRT to sites of microautophagy, as well as the regulatory determinants of their function in TOR signaling. Completion of this work will provide an in-depth understanding of the machinery required for microautophagy. It will shed mechanistic light on novel aspects of DRP and ESCRT function that may have broad implications for membrane remodeling processes in general. Finally, this work will provide important insight into the mechanisms whereby microautophagy regulates TOR signaling. Dysregulation of TOR signaling is associated with several human cancers. Hence, the machinery of microautophagy, as a regulator of TOR signaling, represents a novel target for development of anticancer and antifungal drugs.

微自噬是一种特征不明显的自噬途径，其定义为微自噬细胞的直接内陷， 空泡（真菌）或溶酶体（高等真核生物）膜，用于吞噬和降解 细胞器和胞质组分。微自噬是细胞存活所必需的。 胁迫条件，如营养限制，以及恢复后细胞生长的恢复 因为压力引人注目的是，微自噬也是TOR信号传导的关键调节器， 在生长、生存和寿命控制方面的既定作用。的分子机制 微自噬及其如何调节TOR信号传导尚不清楚。我们的长期目标是 了解微自噬的机制以及微自噬如何被利用来 调节生长和发育所需的信号级联。我们的初步数据 表明微自噬所需的膜重塑取决于 动力蛋白相关蛋白（DRP）Vps1和ESCRTIII组分Snf7。DRP和ESCRT 是迷人的膜重塑机器，对于几种基本的细胞功能至关重要。 包括膜运输、线粒体动力学、胞质分裂和病毒 发芽DRP和ESCRT都将膜变形与自组装相结合。缺陷 在DRP和ESCRT中，由于其在 稳态，包括神经退行性疾病。我们的中心假设是， DRPs和ESCRT之间的功能相互作用形成了膜的分子基础， 微自噬中的内陷此外，我们认为营养和压力信号 途径会聚在Vps1和ESCRT上以调节它们在微自噬中的新功能， 最终控制TOR信号传导和细胞生长。利用遗传学、蛋白质组学、细胞学和 结构的方法，我们将表征招募的机制DRP和ESCRT， 微自噬的位点，以及它们在TOR中功能的调节决定因素 发信号。完成这项工作将使您深入了解机械 微自噬所必需的。它将揭示DRP和ESCRT的新方面的机制光 功能，可能有广泛的影响，膜重塑过程一般。 最后，这项工作将提供重要的洞察机制，微自噬 调节TOR信号传导。TOR信号转导的失调与几种人类免疫缺陷相关。 癌的因此，微自噬机制作为TOR信号传导的调节器，代表了 一个新的抗癌和抗真菌药物的发展目标。