Formation and function of membrane contact sites between the ER and the endocytic pathway

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Membrane contact sites are sites within cells where the membranes of different organelles come very close together, allowing proteins on different organelles to interact directly with each other and also allowing lipids to transfer directly from one organelle to another. We have identified a novel and previously uncharacterised membrane contact site between the endoplasmic reticulum (ER) and endosomes. We know one function of these contacts, which is the interaction between a growth factor receptor on endosomes and a regulatory protein on the ER. Dysregulation of both the growth factor receptor and the regulatory protein have been implicated in human cancer. A likely additional function of these ER:endosome contacts is exchange of cholesterol, as the endosome is the site of cholesterol accumulation derived from the diet and the ER is the site of new cholesterol synthesis. Low cholesterol from the diet stimulates cholesterol synthesis in the ER and so membrane contact sites between endosomes and the ER could be sites of cholesterol sensing. Defects in cholesterol balance underly many human disorders, and contribute to coronary heart disease. This project will identify factors that regulate the formation of membrane contact sites between the ER and endosomes and will develop tools that will allow us to characterise the role of these contact sites in cholesterol sensing and transport. An understanding of the cellular mechanisms underlying membrane contact site formation and cholesterol sensing is the first step towards understanding how those mechanisms are dysregulated under conditions where cholesterol balance is perturbed and how they might be exploited in the design of new therapies.