Abstract 2248 Tracking and functionality of cholesterol pools in cellular membranes

Cells employ regulated transport mechanisms to ensure that their plasma membranes (PMs) are optimally supplied with cholesterol derived from uptake of low-density lipoproteins (LDL) and synthesis. In most animal cells, cholesterol constitutes almost half of all the lipids in the PM. Yet, cholesterol is a potent signaling molecule that controls pathways regulating cellular growth and viability. How can small changes in a molecule present at such high concentrations in the PM be detected to control signaling pathways? The answer lies in how cholesterol is organized in the PM. Most of the PM cholesterol is sequestered through interactions with phospholipids and transmembrane domains of proteins. However, as cholesterol concentration rises above the PM's sequestration capacity, a new pool of cholesterol, called accessible cholesterol, emerges. The transport of accessible cholesterol between the PM and the endoplasmic reticulum (ER) is critical to maintain cholesterol homeostasis and control cell growth. This pathway is also involved in the suppression of both bacterial and viral pathogens by immunomodulatory oxysterols. Today, I will describe aspects of our current work on understanding how cholesterol accessibility in membranes controls diverse signaling pathways. This project was supported by the National Institutes of Health (HL160487 and AI158357), the Welch Foundation (I-1793), and the Leducq Foundation (19CVD04).