Aspergillus fumigatus ffmA Encodes a C(2)H(2)-Containing Transcriptional Regulator That Modulates Azole Resistance and Is Required for Normal Growth.
Aspergillus fumigatus ffmA Encodes a C(2)H(2)-Containing Transcriptional Regulator That Modulates Azole Resistance and Is Required for Normal Growth.
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烟曲霉ffmA编码一个含C（2）H（2）的转录调节因子，可调节唑抗性并为正常生长所需。
DOI：
10.1128/msphere.00938-21
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发表时间：
2022-02-23
期刊：
影响因子：
4.8
通讯作者：
Moye-Rowley WS
中科院分区：
文献类型：
--
作者：
Paul S;Bowyer P;Bromley M;Moye-Rowley WS
与丝状真菌病原菌烟曲霉菌的大量转录因子相对应的缺失突变菌株的产生使得快速鉴定参与一系列不同过程的转录调控因子成为可能。在这里，我们描述了一个被命名为ffmA(有利于发酵代谢)的基因，它是一种含有C2H2的转录因子，是产生唑类耐药性和正常生长所必需的。无论是在未经处理的条件下，还是在唑类挑战的条件下，ffmA的丢失都会导致细胞生长出现明显的缺陷。FfmA的缺失导致了Abcg1ATP结合盒转运蛋白表达的减少，此前有研究表明，该转运蛋白与唑类耐药性有关。引人注目的是，过量生产的atrR转录因子基因使FmAΔ菌株恢复了野生型生长表型。AtrR的过表达也抑制了FfmA缺失引起的Abcg1表达缺陷。用可抑制多西环素的启动子替换ffmA启动子，在没有多西环素的情况下恢复了几乎正常的生长。染色质免疫沉淀实验表明，FfmA与自身启动子结合，也与Abcg1启动子结合。这些数据表明，FfmA和AtrR不仅在Abcg1表达方面相互作用，而且更广泛地调节菌丝生长。与人类主要病原体烟曲霉的唑类耐药形式相关的重要感染与患者群体的不良结局有关。这使得分析烟曲霉产生唑类耐药性的机制成为当务之急。在这项工作中，我们描述了一个名为ffmA的基因的特征，它编码一个序列特异的转录调节因子。我们在一组烟曲霉菌基因缺失突变株的筛选中鉴定了ffmA。FfmA的丢失导致了对唑类药物的敏感性，也导致了正常生长的大幅下降。我们发现过量生产AtrR转录因子可以恢复ffmA缺失细胞的生长。我们提供的证据表明，FfmA可以识别与唑耐药相关的基因的启动子以及ffmA启动子本身。我们的数据表明，FfmA和AtrR相互作用，支持唑类耐药性和正常生长。
The production of a collection of deletion mutant strains corresponding to a large number of transcription factors from the filamentous fungal pathogen Aspergillus fumigatus has permitted rapid identification of transcriptional regulators involved in a range of different processes. Here, we characterize a gene designated ffmA (favors fermentative metabolism) as a C2H2-containing transcription factor that is required for azole drug resistance and normal growth. Loss of ffmA caused cells to exhibit significant defects in growth, either under untreated or azole-challenged conditions. Loss of FfmA caused a reduction in expression of the AbcG1 ATP-binding cassette transporter, previously shown to contribute to azole resistance. Strikingly, overproduction of the AtrR transcription factor gene restored a wild-type growth phenotype to an ffmAΔ strain. Overexpression of AtrR also suppressed the defect in AbcG1 expression caused by loss of FfmA. Replacement of the ffmA promoter with a doxycycline-repressible promoter restored nearly normal growth in the absence of doxycycline. Finally, chromatin immunoprecipitation experiments indicated that FfmA bound to its own promoter as well as to the abcG1 promoter. These data imply that FfmA and AtrR interact both with respect to abcG1 expression and also more broadly to regulate hyphal growth. IMPORTANCE Infections associated with azole-resistant forms of the primary human pathogen Aspergillus fumigatus are associated with poor outcomes in patient populations. This makes analysis of the mechanisms underlying azole resistance of A. fumigatus a high priority. In this work, we describe characterization of a gene designated ffmA that encodes a sequence-specific transcriptional regulator. We identified ffmA in a screen of a collection of gene deletion mutant strains made in A. fumigatus. Loss of ffmA caused sensitivity to azole drugs and also a large reduction in normal growth. We found that overproduction of the AtrR transcription factor could restore growth to ffmA null cells. We provide evidence that FfmA can recognize promoters of genes involved in azole resistance as well as the ffmA promoter itself. Our data indicate that FfmA and AtrR interact to support azole resistance and normal growth.
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影响因子：
11.8
作者：
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影响因子：
11.8
作者：
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通讯作者：
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