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Cellular and Molecular Life Sciences

, Volume 71, Issue 21, pp 4285–4300 | Cite as

The ether lipid precursor hexadecylglycerol protects against Shiga toxins

  • Jonas Bergan
  • Tore Skotland
  • Anne Berit Dyve Lingelem
  • Roger Simm
  • Bjørn Spilsberg
  • Toril Lindbäck
  • Tuulia Sylvänne
  • Helena Simolin
  • Kim Ekroos
  • Kirsten SandvigEmail author
Research Article

Abstract

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.

Keywords

Shiga toxin Globotriaosylceramide Endocytosis Intracellular transport Ether lipids Alkylglycerol 

Notes

Acknowledgments

The work performed by the Oslo group has been supported by South-Eastern Norway Regional Health Authority, The Norwegian Cancer Society, and The Research Council of Norway. We thank Anne-Grethe Myrann for technical assistance with cell experiments, and Sirpa Sutela-Tuominen for assistance with lipidomic experiments.

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Copyright information

© Springer Basel 2014

Authors and Affiliations

  • Jonas Bergan
    • 1
    • 2
    • 3
  • Tore Skotland
    • 1
    • 2
  • Anne Berit Dyve Lingelem
    • 1
    • 2
  • Roger Simm
    • 1
    • 2
  • Bjørn Spilsberg
    • 4
  • Toril Lindbäck
    • 5
  • Tuulia Sylvänne
    • 6
  • Helena Simolin
    • 6
  • Kim Ekroos
    • 6
  • Kirsten Sandvig
    • 1
    • 2
    • 3
    Email author
  1. 1.Centre for Cancer Biomedicine, Faculty of MedicineUniversity of OsloOsloNorway
  2. 2.Department of Biochemistry, Institute for Cancer ResearchThe Norwegian Radium Hospital, Oslo University HospitalOsloNorway
  3. 3.Department of Biosciences, Faculty of Mathematics and Natural SciencesUniversity of OsloOsloNorway
  4. 4.Section of Bacteriology-Food and GMONorwegian Veterinary InstituteOsloNorway
  5. 5.Department of Food Safety and Infection BiologyNorwegian School of Veterinary ScienceOsloNorway
  6. 6.Zora BiosciencesEspooFinland

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