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

微自噬是一种特征不佳的自噬途径，其定义是直接内陷 空泡(真菌)或溶酶体膜(高等真核生物)吞噬和降解 细胞器和细胞质成分。微自噬是细胞存活所必需的 应激条件，如营养限制，以及恢复后细胞生长的恢复 来自压力。引人注目的是，微自噬也是TOR信号的一个关键调节因子，它发挥着 在生长、生存和寿命控制方面发挥着广泛的作用。其分子机制的研究进展 微自噬及其如何调节TOR信号尚不清楚。我们的长期目标是 了解微自噬的机制以及如何利用微自噬 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依赖于 动力蛋白相关蛋白(DRP)Vps1和ESCRTIII组分Snf7。DRP和ESCRT 是令人着迷的膜重塑机器，对几个基本的细胞至关重要 包括膜运输、线粒体动力学、细胞质分裂和病毒在内的过程 萌芽中。DRPs和ESCRT都将膜变形与自组装结合在一起。缺陷 在DRP和ESCRT中，由于它们在 动态平衡，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构成了膜的分子基础 显微自噬中的内陷。此外，我们认为营养和胁迫信号 途径聚集在Vps1和ESCRT上，调节它们在微自噬中的新功能， 最终，控制TOR信号和细胞生长。利用遗传学、蛋白质组学、细胞学和 结构方法，我们将描述DRP和ESCRT的招募机制 微自噬部位及其在TOR中功能的调节决定因素 发信号。这项工作的完成将提供对机械的深入了解 微生物自噬所必需的。它将从机制上阐明DRP和ESCRT的新方面 可能对膜重塑过程有广泛影响的功能。 最后，这项工作将对微自噬的机制提供重要的见解。 调节TOR信号。TOR信号调节失调与几个人类 癌症。因此，微自噬机制作为TOR信号的调节器，代表着 抗癌抗真菌药物开发的新靶点。

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.