Staying in touch with the endocytic network: the importance of contacts for cholesterol transport

Cholesterol homeostasis is critical for cell function and human health. Cholesterol is heterogeneously distributed among cellular membranes, with the redistribution of endocytosed dietary cholesterol playing a pivotal role in the regulation of cholesterol homeostasis. While gaps remain in our understanding of intracellular dietary cholesterol transport, a highly complex network of pathways is starting to emerge, often involving inter‐dependent vesicular and non‐vesicular transport mechanisms. The last decade has seen a surge in interest in non‐vesicular transport and inter‐organellar communication at membrane contact sites. By providing platforms for protein interactions, signalling events, lipid exchange and calcium flux, membrane contact sites (MCS) are now appreciated as controlling the fate of large amounts of lipid and play central roles in the regulation and co‐ordination of endocytic trafficking. Here, we review the role of MCS in multiple pathways for cholesterol export from the endocytic pathway and highlight the intriguing interplay between vesicular and non‐vesicular transport mechanisms and relationship with neurodegenerative disease.
Traffic of dietary cholesterol from the endocytic pathway to the ER is an essential step in cholesterol homeostasis but the mechanism of this cholesterol transport is not completely understood. Sites of contact between the membranes of endocytic and non‐endocytic organelles are emerging as important regulators of both vesicular and non‐vesicular cholesterol transport. Here, we review current understanding of these membrane contact sites and their importance in redistributing dietary cholesterol from endocytic organelles to other cellular membranes and roles in neurodegenerative disease.