Grant: Project Grant

Autophagy is an essential "junk removal" system used by all cells in our bodies to package large objects such as cellular organelles and protein aggregates and deliver these packages to the "cellular incinerator" the lysosome for breakdown. Malfunction of autophagy affects the normal balance between production and breakdown and has been shown to lead to a wide range of human diseases from neurodegeneration, cancer, to infectious diseases. To determine how autophagy is disrupted in the disease state, our laboratory is trying to obtain a comprehensive understanding of how autophagy operates at the molecular level through studying the dedicated protein machinery that coordinates this multi-step process. This project grant application focuses on EPG5, a recently identified component of this machinery that makes sure packages containing the "junk" are correctly delivered to lysosome for breakdown. Furthermore, mutation to EPG5 causes a serious genetic disease called Vici syndrome characterized by incomplete development of the brain and immunodeficiency. Using advanced molecular visualization methods including single-particle electron microscopy (EM) and X-ray crystallography, we will capture the overall shape or detailed molecular structure of this protein. The acquired structural information, together with results from other complementary biochemical and cell-based experiments that we will conduct, will enable us to determine the molecular bases of how EPG5 recognizes the junk packages and the lysosome, and generate mechanistic insights into EPG5's role in autophagy. In the long term, our research will pave the way for the development of autophagy-targeted therapeutics for treating different human diseases, and improve the quality of life of the large number of Canadians suffering from these disorders.