Lipid requirements for entry of protein toxins into cells

The Ether Lipid Precursor Hexadecylglycerol Stimulates the Release and Changes the Composition of Exosomes Derived from PC-3 Cells

“…Furthermore, assuming a diameter of 70 nm for exosomes, PS 18:0_18:1 in the inner leaflet could theoretically occupy ϳ80% of the membrane area occupied by longchain sphingolipids in the outer leaflet of exosomes, and we speculated that this was due to specific interactions between the two membrane leaflets (39). Such interactions might be required for exosome formation and for signaling across the membrane like that observed following binding of Shiga toxin to its lipid receptor on the outer leaflet of cells (54). Interestingly, in this study control exosomes and exosomes released in the presence of DP or HG showed ratios of PS 18:0_18:1 to long-chain sphingolipids (N-amidated C24 and C26 species) fitting with PS 18:0_18:1 and being able to occupy ϳ95, 79, and 71%, respectively, in the inner leaflet of the area covered by these long-chain sphingolipids in the outer leaflet.…”

Shiga toxin glycosphingolipid receptors of Vero-B4 kidney epithelial cells and their membrane microdomain lipid environment

“…However, Stxs entrapped in outer membrane vesicles and binding as well as internalization of toxinloaded vesicles by human intestinal epithelial cells suggest a novel mechanism to deliver pathogenic cargoes and injure host cells ( 101 ). Thus, these novel fi ndings on extracellular transport of AB 5 toxins in lipid vesicles nicely show an unexpected analogy when compared with the intracellular vesicular transportation and retro-translocation of GSL-bound toxins through the Golgi apparatus and the endoplasmic reticulum ( 35 ). However, the potential functional impact of globo-series GSL receptors of Stxs, exposed on the cell surface of target epithelial cells, remains obscure in the process of vesicle internalization at this stage of research.…”

“…Stxs are composed of a single 30 kDa A subunit and a pentamer of noncovalently attached identical 7 kDa B subunits ( 34 ). The B pentamer binds to cell surface-exposed glycosphingolipids (GSLs) of the globo-series and is therefore dependent on these lipids for transport into the cells ( 35 ). After retrograde routing of the holotoxin to the endoplasmic reticulum and cleavage of the A subunit, the A 1 fragment halts eukaryotic protein biosynthesis by inactivating ribosomes leading to cell death ( 36,37 ).…”

“…GSLs preferentially distribute to phase-separated microdomains in the outer leafl et of the plasma membrane, which are suggested to operate as attachment platforms for host pathogens and their toxins on epithelial cells ( 57,92,93 ) to gain entry into cells and retrograde routing to intracellular targets in the cytosol ( 35,56,94 ). The analysis of Average values of triplicate TLC densitometric determinations of three separate experiments of each analyzed GSL in respective sucrose density gradient fractions are listed (see Fig.…”

“…toxin or Stxs from pathogenic E. coli ( 35,56,57 ). Cholesterol-rich lipid rafts make them relatively resistant to solubilization by nonionic detergents, allowing for the isolation of detergent-resistant membranes (DRMs) from low buoyant density fractions after sucrose density ultracentrifugation ( 58 ).…”