tRNA低修饰通过烟曲霉的交叉通路控制系统激活促进5-氟胞嘧啶抗性。

IF 16.6 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Alexander Bruch, Valentina Lazarova, Maximilian Berg, Thomas Krüger, Sascha Schäuble, Abdulrahman A Kelani, Birte Mertens, Pamela Lehenberger, Olaf Kniemeyer, Stefanie Kaiser, Gianni Panagiotou, Fabio Gsaller, Matthew G Blango
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引用次数: 0

摘要

不断增加的抗真菌药物耐药性是与烟曲霉等人类真菌病原体相关的主要问题。基因突变和增殖机制明显驱动耐药性,但表观转录组仍然相对未被测试。在这里,A. fumigatus转移RNA (tRNA)修饰异戊烯基转移酶同源物Mod5的缺失导致应激反应的改变和对抗真菌药物5-氟胞嘧啶(5-FC)的意外抗性。在通过液相色谱-串联质谱和纳米trnaseq确认Mod5的标准异戊烯化活性后,我们进行了转录组和蛋白质组的同步分析,以揭示对5-FC胁迫的可比较的总体反应;然而,在抗真菌治疗后,敲除中交叉通路控制(CPC)基因的过早激活进一步增加。我们在烟曲霉中发现了几个与细粒曲霉主要促进物超家族转运蛋白nmeA同源的特异性CPC-client基因。在Δmod5菌株中,mod5靶点tRNATyrGΨA的过表达挽救了一些表型,但未能逆转5-FC抗性,而nmeA的缺失在很大程度上(但不完全)恢复了抗性表型,这意味着还有其他相关的出口物。总之,在缺乏Mod5和i6A的情况下,5-FC的抗性可能源于多方面的转录和翻译变化,这些变化使真菌倾向于过早地依赖cpc激活抗真菌毒性中间体输出物nmeA,这提供了一种依赖RNA修饰促进短暂抗真菌抗性的潜在机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
tRNA hypomodification facilitates 5-fluorocytosine resistance via cross-pathway control system activation in Aspergillus fumigatus.

Increasing antifungal drug resistance is a major concern associated with human fungal pathogens like Aspergillus fumigatus. Genetic mutation and epimutation mechanisms clearly drive resistance, yet the epitranscriptome remains relatively untested. Here, deletion of the A. fumigatus transfer RNA (tRNA)-modifying isopentenyl transferase ortholog, Mod5, led to altered stress response and unexpected resistance against the antifungal drug 5-fluorocytosine (5-FC). After confirming the canonical isopentenylation activity of Mod5 by liquid chromatography-tandem mass spectrometry and Nano-tRNAseq, we performed simultaneous profiling of transcriptomes and proteomes to reveal a comparable overall response to 5-FC stress; however, a premature activation of cross-pathway control (CPC) genes in the knockout was further increased after antifungal treatment. We identified several orthologues of the Aspergillus nidulans Major Facilitator Superfamily transporter nmeA as specific CPC-client genes in A. fumigatus. Overexpression of Mod5-target tRNATyrGΨA in the Δmod5 strain rescued select phenotypes but failed to reverse 5-FC resistance, whereas deletion of nmeA largely, but incompletely, reverted the resistance phenotype, implying additional relevant exporters. In conclusion, 5-FC resistance in the absence of Mod5 and i6A likely originates from multifaceted transcriptional and translational changes that skew the fungus towards premature CPC-dependent activation of antifungal toxic-intermediate exporter nmeA, offering a potential mechanism reliant on RNA modification to facilitate transient antifungal resistance.

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来源期刊
Nucleic Acids Research
Nucleic Acids Research 生物-生化与分子生物学
CiteScore
27.10
自引率
4.70%
发文量
1057
审稿时长
2 months
期刊介绍: Nucleic Acids Research (NAR) is a scientific journal that publishes research on various aspects of nucleic acids and proteins involved in nucleic acid metabolism and interactions. It covers areas such as chemistry and synthetic biology, computational biology, gene regulation, chromatin and epigenetics, genome integrity, repair and replication, genomics, molecular biology, nucleic acid enzymes, RNA, and structural biology. The journal also includes a Survey and Summary section for brief reviews. Additionally, each year, the first issue is dedicated to biological databases, and an issue in July focuses on web-based software resources for the biological community. Nucleic Acids Research is indexed by several services including Abstracts on Hygiene and Communicable Diseases, Animal Breeding Abstracts, Agricultural Engineering Abstracts, Agbiotech News and Information, BIOSIS Previews, CAB Abstracts, and EMBASE.
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