Link between Heat Shock Protein 90 and the Mitochondrial Respiratory Chain in the Caspofungin Stress Response of Aspergillus fumigatus.

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Serval ID
serval:BIB_27BC0FBB5DCD
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Link between Heat Shock Protein 90 and the Mitochondrial Respiratory Chain in the Caspofungin Stress Response of Aspergillus fumigatus.
Journal
Antimicrobial agents and chemotherapy
Author(s)
Aruanno M., Bachmann D., Sanglard D., Lamoth F.
ISSN
1098-6596 (Electronic)
ISSN-L
0066-4804
Publication state
Published
Issued date
07/2019
Peer-reviewed
Oui
Volume
63
Number
7
Pages
e00208-19.
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
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.
Keywords
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
Pubmed
Web of science
Open Access
Yes
Create date
27/05/2019 17:36
Last modification date
23/06/2020 6:21
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