A Genomewide Screen in Schizosaccharomyces pombe for Genes Affecting the Sensitivity of Antifungal Drugs That Target Ergosterol Biosynthesis
A Genomewide Screen in Schizosaccharomyces pombe for Genes Affecting the Sensitivity of Antifungal Drugs That Target Ergosterol Biosynthesis
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在粟酒裂殖酵母中进行全基因组筛选，寻找影响针对麦角甾醇生物合成的抗真菌药物敏感性的基因
DOI：
10.1128/aac.05126-11
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发表时间：
2012-04-01
影响因子：
4.9
通讯作者：
Kuno, Takayoshi
中科院分区：
文献类型：
--
作者：
Fang, Yue;Hu, Lingling;Kuno, Takayoshi
我们进行了一个全基因组的屏幕改变敏感性的抗真菌药物，包括克霉唑和特比萘芬，目标麦角固醇的生物合成，使用裂殖酵母基因缺失库组成的3,004个非必需的单倍体缺失突变体。我们鉴定了109个过敏突变体和11个对这些抗真菌药有抗性的突变体。缺乏使细胞对这些抗真菌剂敏感的蛋白质被分为各种功能类别，包括麦角固醇生物合成、膜运输、组蛋白乙酰化和脱乙酰化、泛素化、信号转导、核糖体生物合成和组装、转录和翻译的调节、细胞壁组织和生物发生、核糖体功能、氨基酸代谢、核酸代谢、脂质代谢、减数分裂、等功能此外，蛋白质的缺乏，使细胞耐这些抗真菌药被分为功能类别，包括蛋白质的功能，泛素化，膜运输，细胞极性，染色质重塑，和一些未知的功能。此外，测试了109个敏感突变体对米卡芬净的敏感性，米卡芬净是另一种抑制（1，3）-β-D-葡聚糖合酶的抗真菌药物，鉴定出57个超敏感突变体，表明这些突变体在细胞壁完整性方面有缺陷。总之，我们在裂殖酵母中的发现揭示了与麦角固醇生物合成抑制剂的细胞反应相关的分子途径，并可能为开发旨在使细胞对这些药物敏感的策略提供有用的信息。
We performed a genomewide screen for altered sensitivity to antifungal drugs, including clotrimazole and terbinafine, that target ergosterol biosynthesis using a Schizosaccharomyces pombe gene deletion library consisting of 3,004 nonessential haploid deletion mutants. We identified 109 mutants that were hypersensitive and 11 mutants that were resistant to these antifungals. Proteins whose absence rendered cells sensitive to these antifungals were classified into various functional categories, including ergosterol biosynthesis, membrane trafficking, histone acetylation and deacetylation, ubiquitination, signal transduction, ribosome biosynthesis and assembly, regulation of transcription and translation, cell wall organization and biogenesis, mitochondrion function, amino acid metabolism, nucleic acid metabolism, lipid metabolism, meiosis, and other functions. Also, proteins whose absence rendered cells resistant to these antifungals were classified into functional categories including mitochondrion function, ubiquitination, membrane trafficking, cell polarity, chromatin remodeling, and some unknown functions. Furthermore, the 109 sensitive mutants were tested for sensitivity to micafungin, another antifungal drug that inhibits (1,3)-beta-D-glucan synthase, and 57 hypersensitive mutants were identified, suggesting that these mutants were defective in cell wall integrity. Altogether, our findings in fission yeast have shed light on molecular pathways associated with the cellular response to ergosterol biosynthesis inhibitors and may provide useful information for developing strategies aimed at sensitizing cells to these drugs.