Impaired biosynthesis of ergosterol confers resistance to complex sphingolipid biosynthesis inhibitor aureobasidin A in a PDR16-dependent manner
Abstract Complex sphingolipids and sterols are coordinately involved in various cellular functions, e.g. the formation of lipid microdomains. Here we found that budding yeast exhibits resistance to an antifungal drug, aureobasidin A (AbA), an inhibitor of Aur1 catalyzing the synthesis of inositolpho...
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| Format: | Article |
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Nature Portfolio
2023-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-38237-z |
| _version_ | 1797778911367528448 |
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| author | Shizuka Fukuda Yushi Kono Yohei Ishibashi Mitsuaki Tabuchi Motohiro Tani |
| author_facet | Shizuka Fukuda Yushi Kono Yohei Ishibashi Mitsuaki Tabuchi Motohiro Tani |
| author_sort | Shizuka Fukuda |
| collection | DOAJ |
| description | Abstract Complex sphingolipids and sterols are coordinately involved in various cellular functions, e.g. the formation of lipid microdomains. Here we found that budding yeast exhibits resistance to an antifungal drug, aureobasidin A (AbA), an inhibitor of Aur1 catalyzing the synthesis of inositolphosphorylceramide, under impaired biosynthesis of ergosterol, which includes deletion of ERG6 , ERG2, or ERG5 involved in the final stages of the ergosterol biosynthesis pathway or miconazole; however, these defects of ergosterol biosynthesis did not confer resistance against repression of expression of AUR1 by a tetracycline-regulatable promoter. The deletion of ERG6, which confers strong resistance to AbA, results in suppression of a reduction in complex sphingolipids and accumulation of ceramides on AbA treatment, indicating that the deletion reduces the effectiveness of AbA against in vivo Aur1 activity. Previously, we reported that a similar effect to AbA sensitivity was observed when PDR16 or PDR17 was overexpressed. It was found that the effect of the impaired biosynthesis of ergosterol on the AbA sensitivity is completely abolished on deletion of PDR16. In addition, an increase in the expression level of Pdr16 was observed on the deletion of ERG6. These results suggested that abnormal ergosterol biosynthesis confers resistance to AbA in a PDR16-dependent manner, implying a novel functional relationship between complex sphingolipids and ergosterol. |
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| format | Article |
| id | doaj.art-80ebf9e72450416ba6761ce97456f1e6 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-12T23:24:21Z |
| publishDate | 2023-07-01 |
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| spelling | doaj.art-80ebf9e72450416ba6761ce97456f1e62023-07-16T11:15:09ZengNature PortfolioScientific Reports2045-23222023-07-0113111610.1038/s41598-023-38237-zImpaired biosynthesis of ergosterol confers resistance to complex sphingolipid biosynthesis inhibitor aureobasidin A in a PDR16-dependent mannerShizuka Fukuda0Yushi Kono1Yohei Ishibashi2Mitsuaki Tabuchi3Motohiro Tani4Department of Chemistry, Faculty of Sciences, Kyushu UniversityDepartment of Chemistry, Faculty of Sciences, Kyushu UniversityDepartment of Bioscience and Biotechnology, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu UniversityDepartment of Applied Biological Science, Faculty of Agriculture, Kagawa UniversityDepartment of Chemistry, Faculty of Sciences, Kyushu UniversityAbstract Complex sphingolipids and sterols are coordinately involved in various cellular functions, e.g. the formation of lipid microdomains. Here we found that budding yeast exhibits resistance to an antifungal drug, aureobasidin A (AbA), an inhibitor of Aur1 catalyzing the synthesis of inositolphosphorylceramide, under impaired biosynthesis of ergosterol, which includes deletion of ERG6 , ERG2, or ERG5 involved in the final stages of the ergosterol biosynthesis pathway or miconazole; however, these defects of ergosterol biosynthesis did not confer resistance against repression of expression of AUR1 by a tetracycline-regulatable promoter. The deletion of ERG6, which confers strong resistance to AbA, results in suppression of a reduction in complex sphingolipids and accumulation of ceramides on AbA treatment, indicating that the deletion reduces the effectiveness of AbA against in vivo Aur1 activity. Previously, we reported that a similar effect to AbA sensitivity was observed when PDR16 or PDR17 was overexpressed. It was found that the effect of the impaired biosynthesis of ergosterol on the AbA sensitivity is completely abolished on deletion of PDR16. In addition, an increase in the expression level of Pdr16 was observed on the deletion of ERG6. These results suggested that abnormal ergosterol biosynthesis confers resistance to AbA in a PDR16-dependent manner, implying a novel functional relationship between complex sphingolipids and ergosterol.https://doi.org/10.1038/s41598-023-38237-z |
| spellingShingle | Shizuka Fukuda Yushi Kono Yohei Ishibashi Mitsuaki Tabuchi Motohiro Tani Impaired biosynthesis of ergosterol confers resistance to complex sphingolipid biosynthesis inhibitor aureobasidin A in a PDR16-dependent manner Scientific Reports |
| title | Impaired biosynthesis of ergosterol confers resistance to complex sphingolipid biosynthesis inhibitor aureobasidin A in a PDR16-dependent manner |
| title_full | Impaired biosynthesis of ergosterol confers resistance to complex sphingolipid biosynthesis inhibitor aureobasidin A in a PDR16-dependent manner |
| title_fullStr | Impaired biosynthesis of ergosterol confers resistance to complex sphingolipid biosynthesis inhibitor aureobasidin A in a PDR16-dependent manner |
| title_full_unstemmed | Impaired biosynthesis of ergosterol confers resistance to complex sphingolipid biosynthesis inhibitor aureobasidin A in a PDR16-dependent manner |
| title_short | Impaired biosynthesis of ergosterol confers resistance to complex sphingolipid biosynthesis inhibitor aureobasidin A in a PDR16-dependent manner |
| title_sort | impaired biosynthesis of ergosterol confers resistance to complex sphingolipid biosynthesis inhibitor aureobasidin a in a pdr16 dependent manner |
| url | https://doi.org/10.1038/s41598-023-38237-z |
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