Abstract：
Systemic fungal infections are a growing public health threat, and yet viable antifungal drug targets are limited as fungi share a similar proteome with humans. However, features of RNA metabolism and the noncoding transcriptomes in fungi are distinctive. For example, fungi harbor highly structured RNA elements that humans lack, such as self-splicing introns within key housekeeping genes in the mitochondria. However, the location and function of these mitochondrial riboregulatory elements has largely eluded characterization. Here we used an RNA-structure-based bioinformatics pipeline to identify the group I introns interrupting key mitochondrial genes in medically relevant fungi, revealing their fixation within a handful of genetic hotspots and their ubiquitous presence across divergent phylogenies of fungi, including all highest priority pathogens such as Candida albicans, Candida auris, Aspergillus fumigatus and Cryptococcus neoformans. We then biochemically characterized two representative introns from C. albicans and C. auris, demonstrating their exceptionally efficient splicing catalysis relative to previously-characterized group I introns. Indeed, the C. albicans mitochondrial intron displays extremely rapid catalytic turnover, even at ambient temperatures and physiological magnesium ion concentrations. Our results unmask a significant new set of players in the RNA metabolism of pathogenic fungi, suggesting a promising new type of antifungal drug target.
摘要：
系统性真菌感染是一个日益严重的公共卫生威胁，然而，可行的抗真菌药物靶标是有限的，因为真菌与人类共享相似的蛋白质组。然而,真菌中RNA代谢和非编码转录组的特征是独特的。例如,真菌含有人类缺乏的高度结构化的RNA元件，例如线粒体中关键管家基因内的自我剪接内含子。然而,这些线粒体核调节元件的位置和功能在很大程度上没有表征。在这里，我们使用基于RNA结构的生物信息学管道来鉴定干扰医学相关真菌中关键线粒体基因的I组内含子，揭示了它们在少数遗传热点中的固定以及它们在不同的真菌系统发育中的普遍存在，包括所有最优先的病原体，如白色念珠菌，耳念珠菌,烟曲霉和新生隐球菌。然后，我们对来自白色念珠菌和金黄色念珠菌的两个代表性内含子进行了生化鉴定，相对于先前表征的I组内含子，证明了它们异常有效的剪接催化。的确,白色念珠菌线粒体内含子表现出极快的催化周转，即使在环境温度和生理镁离子浓度。我们的结果揭示了病原真菌RNA代谢中一组重要的新参与者，提出了一种有前途的新型抗真菌药物靶标。
