The ether lipid precursor hexadecylglycerol protects against Shiga toxins
| Autor: | Anne Berit Dyve Lingelem, Kirsten Sandvig, Tuulia Sylvänne, Bjørn Spilsberg, Tore Skotland, Kim Ekroos, Roger Simm, Jonas Bergan, Helena Simolin, Toril Lindbäck |
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| Rok vydání: | 2014 |
| Předmět: |
Glycerol
Endosome Palmitic Acid Globotriaosylceramide Golgi Apparatus Glyceryl Ethers Biology Endoplasmic Reticulum Shiga Toxins Endocytosis medicine.disease_cause Ether Glycosphingolipids Cell Line Shiga Toxin Microbiology Inhibitory Concentration 50 Cellular and Molecular Neuroscience chemistry.chemical_compound symbols.namesake Cytosol Escherichia coli medicine Humans Biotinylation Molecular Biology Pharmacology Toxin Trihexosylceramides Endoplasmic reticulum Cell Membrane Biological Transport Shiga toxin Cell Biology Golgi apparatus Lipids Molecular biology HEK293 Cells chemistry symbols biology.protein Molecular Medicine |
| Zdroj: | Cellular and Molecular Life Sciences. 71:4285-4300 |
| ISSN: | 1420-9071 1420-682X |
| DOI: | 10.1007/s00018-014-1624-1 |
| Popis: | Shiga toxin-producing Escherichia coli bacteria cause hemorrhagic colitis and hemolytic uremic syndrome in humans. Currently, only supportive treatment is available for diagnosed patients. We show here that 24-h pretreatment with an ether lipid precursor, the alkylglycerol sn-1-O-hexadecylglycerol (HG), protects HEp-2 cells against Shiga toxin and Shiga toxin 2. Also the endothelial cell lines HMEC-1 and HBMEC are protected against Shiga toxins after HG pretreatment. In contrast, the corresponding acylglycerol, DL-α-palmitin, has no effect on Shiga toxicity. Although HG treatment provides a strong protection (~30 times higher IC₅₀) against Shiga toxin, only a moderate reduction in toxin binding was observed, suggesting that retrograde transport of the toxin from the plasma membrane to the cytosol is perturbed. Furthermore, endocytosis of Shiga toxin and retrograde sorting from endosomes to the Golgi apparatus remain intact, but transport from the Golgi to the endoplasmic reticulum is inhibited by HG treatment. As previously described, HG reduces the total level of all quantified glycosphingolipids to 50-70% of control, including the Shiga toxin receptor globotriaosylceramide (Gb3), in HEp-2 cells. In accordance with this, we find that interfering with Gb3 biosynthesis by siRNA-mediated knockdown of Gb3 synthase for 24 h causes a similar cytotoxic protection and only a moderate reduction in toxin binding (to 70% of control cells). Alkylglycerols, including HG, have been administered to humans for investigation of therapeutic roles in disorders where ether lipid biosynthesis is deficient, as well as in cancer therapy. Further studies may reveal if HG can also have a therapeutic potential in Shiga toxin-producing E. coli infections. |
| Databáze: | OpenAIRE |
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