Scientists discover how cholesterol packing controls cellular transport gates
Researchers found that how tightly lipids pack in cell membranes directly controls whether cells can absorb or transport materials. A single compound that loosens this packing blocks a key cellular process, offering a new mechanism for drug makers to target disease pathways and a framework for understanding how cells physically manage cargo.
Originaltitel: Lipid packing contributes to the confinement of caveolae to the plasma membrane
Lipid packing is a fundamental characteristic of bilayer membranes. It affects all membrane-associated processes ranging from curvature generation to membrane fission. Yet, we lack detailed mechanistic understanding of how lipid packing directly affects these processes in cellular membranes. Here, we address this by focusing on caveolae, small 0-shaped invaginations of the plasma membrane which serve as key regulators of cellular lipid sorting and mechano-responses. In addition to caveolae coat proteins, the lipid membrane is a core component of caveolae that critically impacts both the biogenesis, morphology and stability of such membrane invaginations. We show that the small compound Dyngo-4a adsorbs and inserts into the membrane, resulting in a dramatic dynamin-independent inhibition of caveola dynamics. Analysis of model membranes in combination with molecular dynamics simulations revealed that a substantial amount of Dyngo-4a was inserted and positioned at the level of cholesterol in the bilayer affecting lipid order in a cholesterol dependent manner. Dyngo-4a-treatment resulted in decreased lipid packing of the plasma membrane. This prevented caveolae internalization and lateral diffusion without affecting their morphology, associated proteins, or the overall cell stiffness. Artificially increasing plasma membrane cholesterol levels was found to counteract the block in caveola dynamics caused by Dyngo-4a-mediated lipid packing frustration. Therefore, we propose that the outer leaflet lipid packing of cholesterol in the the plasma membrane critically contributes to the confinement of caveolae to the plasma membrane.