Structure-dependent Pseudoreceptor Intracellular Traffic of Adamantyl Globotriaosyl Ceramide Mimics*
| Autor: | Patty Tam, Anton Novak, Mitsumasa Saito, C A Lingwood, Beth Binnington, Murugespillai Mylvaganum |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Endosome
education Biological Transport Active Adamantane CHO Cells Endosomes Biology medicine.disease_cause Endoplasmic Reticulum Shiga Toxin 1 Biochemistry Jurkat cells Shiga Toxin 2 Cell membrane symbols.namesake Structure-Activity Relationship fluids and secretions Cricetulus Membrane Biology Cricetinae Chlorocebus aethiops medicine Animals Humans Molecular Biology Vero Cells health care economics and organizations Endoplasmic reticulum Trihexosylceramides Cholera toxin Cell Membrane Cell Biology Golgi apparatus Cell biology carbohydrates (lipids) medicine.anatomical_structure Cholesterol HEK293 Cells symbols Vero cell lipids (amino acids peptides and proteins) Intracellular |
| Popis: | The verotoxin (VT) (Shiga toxin) receptor globotriaosyl ceramide (Gb(3)), mediates VT1/VT2 retrograde transport to the endoplasmic reticulum (ER) for cytosolic A subunit access to inhibit protein synthesis. Adamantyl Gb(3) is an amphipathic competitive inhibitor of VT1/VT2 Gb(3) binding. However, Gb(3)-negative VT-resistant CHO/Jurkat cells incorporate adaGb(3) to become VT1/VT2-sensitive. CarboxyadaGb(3), urea-adaGb(3), and hydroxyethyl adaGb(3), preferentially bound by VT2, also mediate VT1/VT2 cytotoxicity. VT1/VT2 internalize to early endosomes but not to Golgi/ER. AdabisGb(3) (two deacyl Gb(3)s linked to adamantane) protects against VT1/VT2 more effectively than adaGb(3) without incorporating into Gb(3)-negative cells. AdaGb(3) (but not hydroxyethyl adaGb(3)) incorporation into Gb(3)-positive Vero cells rendered punctate cell surface VT1/VT2 binding uniform and subverted subsequent Gb(3)-dependent retrograde transport to Golgi/ER to render cytotoxicity (reduced for VT1 but not VT2) brefeldin A-resistant. VT2-induced vacuolation was maintained in adaGb(3)-treated Vero cells, but vacuolar membrane VT2 was lost. AdaGb(3) destabilized membrane cholesterol and reduced Gb(3) cholesterol stabilization in phospholipid liposomes. Cholera toxin GM1-mediated Golgi/ER targeting was unaffected by adaGb(3). We demonstrate the novel, lipid-dependent, pseudoreceptor function of Gb(3) mimics and their structure-dependent modulation of endogenous intracellular Gb(3) vesicular traffic. |
| Databáze: | OpenAIRE |
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