Dissecting the Molecular Mechanisms of Selective Autophagy

受损细胞器和大蛋白质聚集体的积累已被关联 癌症和神经退化等人类疾病。由于规模大、结构复杂， 由于这些胞质组分的性质，它们必须通过专门的囊泡降解 运输途径称为选择性自噬。在选择性自噬中， 被捕获在双膜囊泡内，称为自噬体，并靶向于 空泡或溶酶体降解。虽然大多数运输囊泡的生物发生 通过一个预先存在的膜表面的出芽，选择性的 自噬体通过一个独特的过程发生，其中货物作为模板， 从头小泡生物发生。这些囊泡生物发生事件的分子机制是 大部分未知。我们知识中存在这种差距的主要原因是， 在选择性自噬早期起作用的蛋白质的功能是未知的。此外，本发明还提供了一种方法， 这些蛋白质中的许多缺乏明显的保守结构域，这使得预测蛋白质的结构域具有挑战性。 这些蛋白质的机制。为了研究这些蛋白质的结构和功能， 使用混合结构生物学方法，酵母遗传学，生物化学和细胞生物学。到 补充我们的结构和功能研究，我们将开发一种方法， 选择性自噬这个重组系统最终将使我们能够评估 在囊泡生物发生的每个阶段都需要选择性自噬因子。通过这些 不同的调查，我们将建立一个全面的描述的分子 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 对选择性自噬与人类免疫系统之间复杂关系的宝贵见解 疾病

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.