Small regulators, major consequences – Ca2+ and cholesterol at the endosome–ER interface

The ER is the largest cellular compartment and a major storage site for lipids and ions. In recent years, much attention has focused on contacts between the ER and other organelles, and one particularly intimate relationship is that between the ER and the endosomal system. ER–endosome contacts intensify when endosomes mature, and the ER participates in endosomal processes, such as the termination of surface receptor signaling, multi-vesicular body formation, and transport and fusion events. Cholesterol and Ca2+ are transferred between the ER and endosomes, possibly acting as messengers for ER–endosome crosstalk. Here, we summarize different types of ER–endosomal communication and discuss membrane contact sites that might facilitate this crosstalk. We review the protein pairs that interact at the ER–endosome interface and find that many of these have a role in cholesterol exchange. We also summarize Ca2+ exchange between the ER and endosomes, and hypothesize that ER–endosome contacts integrate several cellular functions to guide endosomal maturation. We post the hypothesis that failure in ER–endosome contacts is an unrecognized but important contributor to diseases, such as Niemann–Pick type C disease, Alzheimer's disease and amyotrophic lateral sclerosis.