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

膜接触位点是细胞内不同细胞器的膜非常接近的位点，允许不同细胞器上的蛋白质直接相互作用，也允许脂质直接从一个细胞器转移到另一个细胞器。我们已经确定了一个新的和以前未表征的膜接触点之间的内质网（ER）和内体。我们知道这些接触的一个功能，即内体上的生长因子受体和ER上的调节蛋白之间的相互作用。生长因子受体和调节蛋白的失调与人类癌症有关。这些ER：内体接触的一个可能的额外功能是胆固醇的交换，因为内体是源自饮食的胆固醇积累的位点，而ER是新胆固醇合成的位点。饮食中的低胆固醇刺激ER中的胆固醇合成，因此内体和ER之间的膜接触位点可能是胆固醇传感位点。胆固醇平衡的缺陷是许多人类疾病的基础，并导致冠心病。该项目将确定调节ER和内体之间膜接触位点形成的因素，并将开发工具，使我们能够验证这些接触位点在胆固醇传感和运输中的作用。了解膜接触位点形成和胆固醇传感的细胞机制是了解这些机制在胆固醇平衡受到干扰的条件下如何失调以及如何在新疗法的设计中利用它们的第一步。

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.