Lipid packing and cholesterol content regulate membrane wetting and remodeling by biomolecular condensates

Abstract Biomolecular condensates play a pivotal role in cellular processes by interacting with membranes and leading to wetting transitions and to mutual remodeling. Using a combination of hyperspectral imaging, phasor analysis, and fluid-elastic parameter measurements, we investigated how membrane lipid packing affects condensate wetting. Our results show that it is not only the membrane phase state, but rather the degree of lipid packing that determines the condensate affinity for membranes. Increasing lipid chain length or cholesterol content enhances lipid packing, thereby decreasing condensate affinity. This regulatory mechanism is consistent across various condensate-membrane systems, underscoring the critical role of the membrane interface. Additionally, protein adsorption promotes extensive membrane remodeling, including tube and double-membrane sheet formation. This work provides a novel mechanism by which membrane composition fine-tunes condensate wetting, highlighting its potential impact on cellular functions and organelle interactions.