Link between Heat Shock Protein 90 and the Mitochondrial Respiratory Chain in the Caspofungin Stress Response of Aspergillus fumigatus
| Autor: | Dominique Sanglard, Daniel Bachmann, Frédéric Lamoth, Marion Aruanno |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Antifungal Agents
Echinocandin Pharmacology Aspergillus fumigatus Electron Transport Fungal Proteins 03 medical and health sciences chemistry.chemical_compound Echinocandins Caspofungin Mechanisms of Resistance Heat shock protein Gene Expression Regulation Fungal Rotenone medicine polycyclic compounds Pharmacology (medical) HSP90 Heat-Shock Proteins skin and connective tissue diseases 030304 developmental biology Voriconazole 0303 health sciences biology 030306 microbiology Geldanamycin biochemical phenomena metabolism and nutrition biology.organism_classification bacterial infections and mycoses Hsp90 Mitochondria Antifungal Agents/pharmacology Aspergillus fumigatus/drug effects Aspergillus fumigatus/metabolism Caspofungin/pharmacology Echinocandins/pharmacology Electron Transport/drug effects Electron Transport/physiology Fungal Proteins/metabolism Gene Expression Regulation Fungal/drug effects HSP90 Heat-Shock Proteins/metabolism Mitochondria/drug effects Mitochondria/metabolism Rotenone/pharmacology NADH-ubiquinone oxidoreductases echinocandins invasive aspergillosis mitochondria paradoxical effect rotenone transcriptomics Infectious Diseases Mitochondrial respiratory chain chemistry biology.protein medicine.drug |
| Zdroj: | Antimicrobial agents and chemotherapy, vol. 63, no. 7, pp. e00208-19. |
| ISSN: | 1098-6596 |
| Popis: | Aspergillus fumigatus is an opportunistic mold responsible for invasive aspergillosis. Triazoles (e.g., voriconazole) represent the first-line treatment, but emerging resistance is of concern. The echinocandin drug caspofungin is used as second-line treatment but has limited efficacy. The heat shock protein 90 (Hsp90) orchestrates the caspofungin stress response and is the trigger of an adaptive phenomenon called the paradoxical effect (growth recovery at increasing caspofungin concentrations). The aim of this study was to elucidate the Hsp90-dependent mechanisms of the caspofungin stress response. Transcriptomic profiles of the wild-type A. fumigatus strain (KU80) were compared to those of a mutant strain with substitution of the native hsp90 promoter by the thiA promoter (pthiA-hsp90), which lacks the caspofungin paradoxical effect. Caspofungin induced expression of the genes of the mitochondrial respiratory chain (MRC), in particular, NADH-ubiquinone oxidoreductases (complex I), in KU80 but not in the pthiA-hsp90 mutant. The caspofungin paradoxical effect could be abolished by rotenone (MRC complex I inhibitor) in KU80, supporting the role of MRC in the caspofungin stress response. Fluorescent staining of active mitochondria and measurement of oxygen consumption and ATP production confirmed the activation of the MRC in KU80 in response to caspofungin, but this activity was impaired in the pthiA-hsp90 mutant. Using a bioluminescent reporter for the measurement of intracellular calcium, we demonstrated that inhibition of Hsp90 by geldanamycin or MRC complex I by rotenone prevented the increase in intracellular calcium shown to be essential for the caspofungin paradoxical effect. In conclusion, our data support a role of the MRC in the caspofungin stress response which is dependent on Hsp90. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|