Tamoxifen blocks retrograde trafficking of Shiga toxin 1 and 2 and protects against lethal toxicosis
| Autor: | Andrey S. Selyunin, Stanton F. McHardy, Steven Hutchens, Somshuvra Mukhopadhyay |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Endosome
Health Toxicology and Mutagenesis Intracellular Space Estrogen receptor Golgi Apparatus Plant Science Endosomes medicine.disease_cause Shiga Toxin 1 Biochemistry Genetics and Molecular Biology (miscellaneous) Shiga Toxin 2 03 medical and health sciences fluids and secretions 0302 clinical medicine medicine Autophagy Humans Escherichia coli Research Articles 030304 developmental biology 0303 health sciences Ecology biology Toxin Chemistry Lethal dose Shiga toxin 3. Good health Protein Transport Tamoxifen Hemolytic-Uremic Syndrome biology.protein Cancer research Signal transduction Lysosomes 030217 neurology & neurosurgery Research Article HeLa Cells Signal Transduction |
| Zdroj: | Life Science Alliance |
| ISSN: | 2575-1077 |
| Popis: | This study reports an unexpected role of late endosome–lysosome fusion in early endosome-to-Golgi trafficking of Shiga toxins and identifies tamoxifen to be a potent inhibitor of Shiga toxicosis. Shiga toxin 1 (STx1) and 2 (STx2), produced by Shiga toxin–producing Escherichia coli, cause lethal untreatable disease. The toxins invade cells via retrograde trafficking. Direct early endosome-to-Golgi transport allows the toxins to evade degradative late endosomes. Blocking toxin trafficking, particularly at the early endosome-to-Golgi step, is appealing, but transport mechanisms of the more disease-relevant STx2 are unclear. Using data from a genome-wide siRNA screen, we discovered that disruption of the fusion of late endosomes, but not autophagosomes, with lysosomes blocked the early endosome-to-Golgi transport of STx2. A subsequent screen of clinically approved lysosome-targeting drugs identified tamoxifen (TAM) to be a potent inhibitor of the trafficking and toxicity of STx1 and STx2 in cells. The protective effect was independent of estrogen receptors but dependent on the weak base property of TAM, which allowed TAM to increase endolysosomal pH and alter endosomal dynamics. Importantly, TAM treatment enhanced survival of mice injected with a lethal dose of STx1 or STx2. Thus, it may be possible to repurpose TAM for treating Shiga toxin–producing E. coli infections. |
| Databáze: | OpenAIRE |
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