My lab investigates the routes and mechanisms of cholesterol trafficking inside cells and how alterations in this trafficking affect cellular activities.
Cholesterol plays a critical role in the structure and function of mammalian cell membranes and is so important that cells either import cholesterol from the outside or make cholesterol in the endoplasmic reticulum. Either way, the proper amount of cholesterol must be delivered to different membranes in the cell. Consequently, cholesterol trafficking is very complicated and must be tightly regulated, and the exact routes and mechanisms of this intracellular cholesterol traffic are still unclear. Our research focuses on the role of membrane tubules, which may be involved at different points in protein trafficking. Membrane tubules can be an efficient and effective way to rapidly deliver large batches of cholesterol to specific locations without disturbing the existing composition of membranes. When we inhibited the formation of membrane tubules, the distributions of several proteins involved in the regulation of membrane traffic were altered. More importantly, the distribution of intracellular cholesterol was also altered, and cholesterol accumulated in a compartment known as the recycling endosome. This accumulation only occurred when there was a certain level of cholesterol in the plasma membrane. These results allowed us to delineate a route that at least some free cholesterol follows when it is imported into cells.
We also found that the distribution of several proteins that preferentially associate with cholesterol are also affected by the inhibition of membrane tubules. One such protein is amyloid precursor protein (APP), which, when processed by a particular protein complex, results in Alzheimer's Disease. Cholesterol has been implicated in this process, but the mechanism is not clear. When membrane tubules are inhibited, APP colocalizes with cholesterol in the recycling endosome, but not with the protein complex. Surprisingly, we found that APP does colocalize with the complex when the import of cholesterol into cells is significantly decreased. This is the focus of our current research. A second focus of our research involves the integration of the synthetic and imported cholesterol pathways.