Joost Holthuis (University of Osnabrück)

Interrogating lipid dynamics at sites of membrane permeabilization and repair

Host: Frank Glorius

Having a soft membrane bilayer as their only cover, mammalian cells are vulnerable to injuries from diverse materials but also accessible to controlled forms of permeabilization to meet therapeutic needs. As even minor perforations of the plasma membrane (PM) pose a threat to cell viability, robust membrane repair mechanisms evolved to restore the integrity of permeabilized cells and promote their survival. We previously uncovered a sphingomyelin (SM)-based membrane repair pathway that functions independently of ESCRT to reverse potentially lethal damage of lysosomes. Minor perturbations in lysosome integrity inflicted by chemicals or pathogens are tightly coupled to a Ca2+-activated scrambling and cytosolic exposure of SM. Subsequent metabolic conversion of SM into ceramide by neutral SMase2 in the cytosolic leaflet promotes clearance of membrane lesions, likely involving an intraluminal shedding of the damaged area. Using a chemical strategy for imaging lipid flows inside living cells, we found that lysosomal repair critically relies on a non-vesicular supply of bulk lipids from the ER. Removal of nSMase2 or blocking Ca2+-activated lipid scrambling at the PM renders cells sensitive to perforation by toxins or a laser, suggesting that a SM-based repair mechanism also operates at the PM. How a transient subversion of lipid asymmetry contributes to the restoration of wounded cells is a major focus of our ongoing work. Additionally, we investigate how distinct classes of supramolecular materials mediate a non-lytic PM passage of polar peptides. Insights into how these carriers disrupt the PM barrier and how cells respond to this breach in structural integrity may benefit the development of novel therapeutic strategies.

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