ABCA1 transporter reduces amphotericin B cytotoxicity in mammalian cells
| Autor: | Yannick Hamon, Giovanna Chimini, Rafal Luchowski, Wiesław I. Gruszecki, Wojciech Grudzinski, A. Szczepaniak, Ewa Grela, Nina Filipczak, Mariusz Gagoś, Tomasz Trombik, Ambroise Wu, Karolina Wojtowicz, Olga Raducka-Jaszul |
|---|---|
| Přispěvatelé: | Sol Agro et hydrosystème Spatialisation (SAS), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Cell
chemistry.chemical_compound Mice MTT cytotoxicity assays Ergosterol Raw 264.7 macrophages Cytotoxicity 0303 health sciences biology 030302 biochemistry & molecular biology Lipids Cell biology medicine.anatomical_structure Cholesterol Molecular Medicine [SDV.IMM]Life Sciences [q-bio]/Immunology lipids (amino acids peptides and proteins) Original Article Efflux medicine.symptom Plasma membrane ATP Binding Cassette Transporter 1 FLIM CHO Cells 03 medical and health sciences Cellular and Molecular Neuroscience Cricetulus Amphotericin B Lipid translocation medicine Animals Humans Molecular Biology Cell Proliferation Pharmacology Cell Membrane technology industry and agriculture Cell Biology bacterial infections and mycoses RAW 264.7 Cells Mechanism of action chemistry Gene Expression Regulation Cell culture ABCA1 CHO-K1 biology.protein Mutant Proteins Fluorescence anisotropy |
| Zdroj: | Cellular and Molecular Life Sciences CELLULAR AND MOLECULAR LIFE SCIENCES CELLULAR AND MOLECULAR LIFE SCIENCES, 2019, 76 (24), pp.4979-4994. ⟨10.1007/s00018-019-03154-w⟩ |
| ISSN: | 1420-9071 1420-682X |
| Popis: | Amphotericin B (AmB) belongs to a group of polyene antibiotics commonly used in the treatment of systemic mycotic infections. A widely accepted mechanism of action of AmB is based on the formation of an oligomeric pore structure within the plasma membrane (PM) by interaction with membrane sterols. Although AmB binds preferentially to ergosterol, it can also bind to cholesterol in the mammalian PM and cause severe cellular toxicity. The lipid content and its lateral organization at the cell PM appear to be significant for AmB binding. Several ATP-binding cassette (ABC) transporters, including ABCA1, play a crucial role in lipid translocation, cholesterol redistribution and efflux. Here, we demonstrate that cells expressing ABCA1 are more resistant to AmB treatment, while cells lacking ABCA1 expression or expressing non-active ABCA1MM mutant display increased sensitivity. Further, a FLIM analysis of AmB-treated cells reveals a fraction of the antibiotic molecules, characterized by relatively high fluorescence lifetimes (> 6 ns), involved in formation of bulk cholesterol–AmB structures at the surface of ABCA1-expressing cells. Finally, lowering the cellular cholesterol content abolishes resistance of ABCA1-expressing cells to AmB. Therefore, we propose that ABCA1-mediated cholesterol efflux from cells induces formation of bulk cholesterol–AmB structures at the cell surface, preventing AmB cytotoxicity. Electronic supplementary material The online version of this article (10.1007/s00018-019-03154-w) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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