Regulation of VPS34 Kinase in Response to Starvation

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Lay Summary The ability of cells to respond to changes in nutrient availability is essential for the maintenance of promoting survival and balancing energy expenditure with intake. One of the most important ways for cells to generate energy under starvation is to activate a process called autophagy (literally meaning “self-eating”). In this process the cell degrades a small portion of its interior to generate nutrients required for survival. One of the most important enzymes in this process is the lipid kinase VPS34, which phosphorylates lipids required for the formation of the destructive autophagic vesicle. We have recently discovered that the phosphorylation of lipids by VPS34 on another vesicle called the endosome is also required for survival under starvation. This is quite interesting as the endosome has no direct way of generating energy or known way of reducing energy expenditure. In this research program we will find out how the cell transmits information to endosomal VPS34 and what the downstream effects of this regulation are. Moreover, we will determine how this promotes survival under starvation. This is an exciting area of research because up to this point nearly all the studies on this kinase have been on its role in the autophagy pathway. It is also interesting because we can see that taking away different nutrients all have the same effect of reducing the efficiency of the endosomal VPS34 kinase, indicating that this type of regulation is likely a core aspect of the starvation response. Moving forward from this study we will determine how this pathway interacts with other metabolic stress responses looking for cross-talk or feedback. We will also move our metabolic studies from the cellular to the organismal level to get a more comprehensive understanding of this process in different tissues and forms of nutrient restriction. These studies will fill an important gap in our understanding of the mammalian starvation response.