Elucidating the conserved role of palmitoylation in autophagy.

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The cell is the smallest unit that makes up organs and tissues and it is important to understand the mechanisms that are required for cell survival. One crucial mechanism for cell survival is known as autophagy, which simply means "self-eating." It refers to how cells degrade non-functional components that might become toxic to the cell. Autophagy can also recycle these materials for energy during starvation. As such, autophagy is sometimes referred to as the trash bin or garburator of the cell. When non-functional components build up they can become toxic, much like an overflowing garburator. Therefore, it is important to understand how autophagy functions at the molecular level in the cell, particularly within the nervous system where neurons are more susceptible to cell death when autophagy is disrupted. Autophagy is present in all organisms that contain a nucleus, a compartment storing DNA. This includes essentially anything that is not bacteria or virus - from yeast to humans. Therefore, understanding autophagy even in the simplest organism, like yeast, can have applications in humans. Autophagy is dependent on proteins to properly localise within the cell to specialised compartments known as organelles. In autophagy, an organelle known as the autophagosome encompasses the toxic molecules and delivers them to the lysosome, an acidic organelle, to be degraded, like in a garburator. One way that proteins are targeted to different organelles is by adding small modifications to proteins, like a fat or lipid. One of these lipid modifications of protein is referred to as palmitoylation. Palmitoylation is unique among fatty modifications because it can be also be removed from proteins, making it dynamic. So, palmitoylated proteins can be released from organelles by removing the palmitoylation modification on the protein. The goal of my research program is to determine the molecular basis of the cellular signaling process of palmitoylation in autophagy and how it is conserved from yeast to mammals by pursuing the following aims. Aim 1 - Identify the proteins/enzymes that mediate palmitoylation during autophagy. Aim 2 - Determine how palmitoylation regulates autophagy. Aim 3 - Characterise how fat in the affects palmitoylation in autophagy. Students and trainees will gain valuable skills in biochemistry and cell biology including unique palmitoylation assays that can be performed in any biological tissue as well as high resolution cell imaging techniques. This research will provide new insights into the crucial mechanism of how proteins are targeted to membranes in autophagy. Knowledge from simple organisms will be applied to more complex ones to determine how autophagy is regulated in the nervous system. Ultimately, it will also provide details of how diet may regulate these important pathways.