Dissecting the Molecular Mechanisms of Selective Autophagy

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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.