The genome of tolypocladium inflatum: evolution, organization, and expression of the cyclosporin biosynthetic gene cluster.
The genome of tolypocladium inflatum: evolution, organization, and expression of the cyclosporin biosynthetic gene cluster.
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DOI：
10.1371/journal.pgen.1003496
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发表时间：
2013-06
期刊：
影响因子：
4.5
通讯作者：
Spatafora JW
中科院分区：
文献类型：
--
作者：
Bushley KE;Raja R;Jaiswal P;Cumbie JS;Nonogaki M;Boyd AE;Owensby CA;Knaus BJ;Elser J;Miller D;Di Y;McPhail KL;Spatafora JW
子囊真菌Tolypocladium inflatum是甲虫幼虫的病原体，它最著名的是生产免疫抑制剂环孢菌素。T.本文沿着介绍了首次分离出环孢菌素的胀囊霉菌株NRRL 8044（ATCC 34921）的环孢菌素和其它次级代谢产物的生物合成的比较分析。胀囊藻和相关分类群。系统基因组分析揭示了编码环孢菌素合成酶（simA）的非核糖体肽合成酶（NRPS）与具有抗昆虫活性的其他次级代谢物（例如，白僵菌素、destruxins等），阐明了模块复制和基因融合在NRPS多样性中的作用。描述了负责环孢菌素生物合成的次级代谢物基因簇。除了环孢菌素生物合成所必需的基因外，它还含有亲环素的基因，亲环素是已知结合环孢菌素的亲免疫素家族的成员。比较分析支持谱系特异性起源的环孢菌素基因簇，而不是从细菌或其他真菌的水平基因转移。在环孢菌素诱导培养基中的RNA-Seq转录组分析描绘了环孢菌素簇的边界，并揭示了基因簇亲环素的高水平表达。在含有昆虫血淋巴的培养基中，观察到环孢菌素簇内的几个基因（包括高表达的亲环素基因）的较弱但显著的上调。T. inflatum还代表了蛇果菌科（Ophiocordycipitaceae）的第一个参考基因组草图，蛇果菌科是真菌目肉座菌目（Hypocreales）内的第三个昆虫病原真菌科，并支持昆虫病原体的平行和定性不同的辐射。霸王inflatum基因组为进一步研究环孢菌素的进化和生物合成提供了新的视角，并为进一步研究次级代谢产物基因簇及其代谢产物在真菌生物学中的作用奠定了基础。 Tolypocladium inflatum是一种真菌，从中分离出免疫抑制剂药物环孢菌素，是一种多产的次级代谢产物，在医学和农业方面具有潜在的应用。我们已经完成了T. inflatum，这也代表了一个新的家庭的昆虫病原真菌，Ophiocordycipitaceae的第一个基因组。我们提出了比较基因组和进化分析的环孢菌素非核糖体肽合成酶（simA），突出的谱系特异性性质的环孢菌素的起源和同源性的环孢菌素腺苷酸化（A）结构域与其他真菌NRPS的产品显示抗昆虫活性。RNA-Seq数据描绘了环孢菌素基因簇在诱导培养基中以及响应于模拟昆虫发病的不同阶段的培养基的表达模式。T. inflatum基因组揭示了负责环孢菌素生物合成的代谢物基因簇，并描述了其进化的复杂模式。
The ascomycete fungus Tolypocladium inflatum, a pathogen of beetle larvae, is best known as the producer of the immunosuppressant drug cyclosporin. The draft genome of T. inflatum strain NRRL 8044 (ATCC 34921), the isolate from which cyclosporin was first isolated, is presented along with comparative analyses of the biosynthesis of cyclosporin and other secondary metabolites in T. inflatum and related taxa. Phylogenomic analyses reveal previously undetected and complex patterns of homology between the nonribosomal peptide synthetase (NRPS) that encodes for cyclosporin synthetase (simA) and those of other secondary metabolites with activities against insects (e.g., beauvericin, destruxins, etc.), and demonstrate the roles of module duplication and gene fusion in diversification of NRPSs. The secondary metabolite gene cluster responsible for cyclosporin biosynthesis is described. In addition to genes necessary for cyclosporin biosynthesis, it harbors a gene for a cyclophilin, which is a member of a family of immunophilins known to bind cyclosporin. Comparative analyses support a lineage specific origin of the cyclosporin gene cluster rather than horizontal gene transfer from bacteria or other fungi. RNA-Seq transcriptome analyses in a cyclosporin-inducing medium delineate the boundaries of the cyclosporin cluster and reveal high levels of expression of the gene cluster cyclophilin. In medium containing insect hemolymph, weaker but significant upregulation of several genes within the cyclosporin cluster, including the highly expressed cyclophilin gene, was observed. T. inflatum also represents the first reference draft genome of Ophiocordycipitaceae, a third family of insect pathogenic fungi within the fungal order Hypocreales, and supports parallel and qualitatively distinct radiations of insect pathogens. The T. inflatum genome provides additional insight into the evolution and biosynthesis of cyclosporin and lays a foundation for further investigations of the role of secondary metabolite gene clusters and their metabolites in fungal biology. Tolypocladium inflatum, the fungus from which the immunosuppressant drug cyclosporin was isolated, is a prolific producer of secondary metabolites with potential applications in medicine and agriculture. We have sequenced the first draft reference genome of T. inflatum, which also represents the first genome of a novel family of insect pathogenic fungi, Ophiocordycipitaceae. We present comparative genomic and evolutionary analyses of the cyclosporin nonribosomal peptide synthetase (simA), which highlight the lineage specific nature of cyclosporin's origin and the homology of cyclosporin adenylation (A) domains with other fungal NRPSs whose products show anti-insect activity. RNA-Seq data profiles the expression patterns of the cyclosporin gene cluster in an inducing medium and in response to media simulating distinct stages of insect pathogenesis. Sequencing of the T. inflatum genome has uncovered the metabolite gene cluster responsible for cyclosporin biosynthesis and characterized complex patterns of its evolution.
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