Dissecting the Molecular Mechanisms of Selective Autophagy

摘要 受损的细胞器和大的蛋白质聚集体的积累是相关的。 包括癌症和神经变性在内的人类疾病。由于规模庞大而复杂 这些胞液成分的性质，它们必须通过一个特殊的囊泡来降解 运输途径被称为选择性自噬。在选择性自噬中，大的胞浆物质 被捕获在双膜囊泡中，称为自噬小体，并针对 用于降解的液泡或溶酶体。而大多数运输小泡的生物发生 通过预先存在的膜表面的萌发，选择性的 自噬通过一个不同的过程发生，在这个过程中，货物充当 从新的囊泡生物发生。这些囊泡生物发生事件的分子机制是 很大程度上是未知的。我们认识上这种差距的主要原因是结构和 选择性自噬早期发挥作用的蛋白质的功能尚不清楚。此外, 其中许多蛋白质缺乏明显的保守结构域，这使得预测 这些蛋白质的机制。为了研究这些蛋白质的结构和功能，我们将 使用杂交结构生物学方法、酵母遗传学、生物化学和细胞生物学。至 补充我们的结构和功能研究，我们将开发一种方法来重建 选择性自噬。这个重建系统最终将使我们能够评估 囊泡生物发生的每个阶段都需要选择性的自噬因子。通过这些 不同的调查，我们将建立一个全面的分子描述 选择性自噬的机制。随着选择性自噬越来越多地与 对于人类疾病，确定选择性自噬的机制也将提供 对选择性自噬和人类之间复杂关系的宝贵见解 疾病。

Abstract The accumulation of damaged organelles and large protein aggregates has been correlated with human diseases including cancer and neurodegeneration. Due to the large and complex nature of these cytosolic components, they must be degraded through a specialized vesicle trafficking pathway termed selective autophagy. In selective autophagy, large cytosolic material is captured within double membrane vesicles, termed autophagosomes, and targeted to the vacuole or lysosome for degradation. While the biogenesis of most trafficking vesicles occurs through the budding of a preexisting membrane surface, the biogenesis of the selective autophagosome occurs through a distinct process in which the cargo serves as a template for de novo vesicle biogenesis. The molecular mechanisms of these vesicle biogenesis events are largely unknown. The primary reason for this gap in our knowledge is that the structure and function of the proteins which function early in selective autophagy are unknown. In addition, many of these proteins lack obvious conserved domains which makes it challenging to predict a mechanism for these proteins. To investigate the structure and function of these proteins we will use hybrid structural biology methods, yeast genetics, biochemistry and cell biology. To complement our structure and function studies we will develop a method to reconstitute selective autophagy. This reconstitution system will ultimately enable us to evaluate what selective autophagy factors are required at each stage of vesicle biogenesis. Through these diverse investigations, we will establish a comprehensive description of the molecular mechanisms of selective autophagy. As selective autophagy has been increasingly correlated with human diseases, determining the mechanisms of selective autophagy will also provide invaluable insight into the complicated relationship between selective autophagy and human disease.