Dysfunction of Prohibitin 2 Results in Reduced Susceptibility to Multiple Antifungal Drugs via Activation of the Oxidative Stress-Responsive Transcription Factor Pap1 in Fission Yeast
| Autor: | Yue Fang, Lina Zhou, Si Chen, Guanglie Jiang, Qiannan Liu, Min Xu, Fan Yao, Norihiro Sakamoto, Takayoshi Kuno |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Antifungal Agents Antifungal drug Mitochondrion Nitric Oxide 03 medical and health sciences Drug Resistance Fungal Mechanisms of Resistance Gene Expression Regulation Fungal Prohibitins Schizosaccharomyces Gene expression Pharmacology (medical) RNA Messenger Clotrimazole Prohibitin Terbinafine Gene Transcription factor Pharmacology biology Chemistry biology.organism_classification Cell biology Repressor Proteins Oxidative Stress Basic-Leucine Zipper Transcription Factors 030104 developmental biology Infectious Diseases Schizosaccharomyces pombe Schizosaccharomyces pombe Proteins Reactive Oxygen Species Transcription Factors Genetic screen |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 62 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | The fight against resistance to antifungal drugs requires a better understanding of the underlying cellular mechanisms. In order to gain insight into the mechanisms leading to antifungal drug resistance, we performed a genetic screen on a model organism, Schizosaccharomyces pombe, to identify genes whose overexpression caused resistance to antifungal drugs, including clotrimazole and terbinafine. We identified the phb2(+) gene, encoding a highly conserved mitochondrial protein, prohibitin (Phb2), as a novel determinant of reduced susceptibility to multiple antifungal drugs. Unexpectedly, deletion of the phb2(+) gene also exhibited antifungal drug resistance. Overexpression of the phb2(+) gene failed to cause drug resistance when the pap1(+) gene, encoding an oxidative stress-responsive transcription factor, was deleted. Furthermore, pap1(+) mRNA expression was significantly increased when the phb2(+) gene was overexpressed or deleted. Importantly, either overexpression or deletion of the phb2(+) gene stimulated the synthesis of NO and reactive oxygen species (ROS), as measured by the cell-permeant fluorescent NO probe DAF-FM DA (4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate) and the ROS probe DCFH-DA (2′,7′-dichlorodihydrofluorescein diacetate), respectively. Taken together, these results suggest that Phb2 dysfunction results in reduced susceptibility to multiple antifungal drugs by increasing NO and ROS synthesis due to dysfunctional mitochondria, thereby activating the transcription factor Pap1 in fission yeast. |
| Databáze: | OpenAIRE |
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