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Heptahelical Receptors GprC and GprD of Aspergillus fumigatus Are Essential Regulators of Colony Growth, Hyphal Morphogenesis, and Virulence

机译:烟曲霉的庚六肽受体GprC和GprD是菌落生长,菌丝形态发生和毒力的重要调节剂。

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The filamentous fungus Aspergillus fumigatus normally grows on compost or hay but is also able to colonize environments such as the human lung. In order to survive, this organism needs to react to a multitude of external stimuli. Although extensive work has been carried out to investigate intracellular signal transduction in A. fumigatus , little is known about the specific stimuli and the corresponding receptors activating these signaling cascades. Here, two putative G-protein-coupled receptors, GprC and GprD, were characterized with respect to their cellular functions. Deletion of the corresponding genes resulted in drastic growth defects as hyphal extension was reduced, germination was retarded, and hyphae showed elevated levels of branching. The growth defect was found to be temperature dependent. The higher the temperature the more pronounced was the growth defect. Furthermore, compared with the wild type, the sensitivity of the mutant strains toward environmental stress caused by reactive oxygen intermediates was increased and the mutants displayed an attenuation of virulence in a murine infection model. Both mutants, especially the Δ gprC strain, exhibited increased tolerance toward cyclosporine, an inhibitor of the calcineurin signal transduction pathway. Transcriptome analyses indicated that in both the gprC and gprD deletion mutants, transcripts of primary metabolism genes were less abundant, whereas transcription of several secondary metabolism gene clusters was upregulated. Taken together, our data suggest the receptors are involved in integrating and processing stress signals via modulation of the calcineurin pathway.
机译:丝状真菌烟曲霉通常在堆肥或干草上生长,但也能够在人肺等环境中定殖。为了生存,这种生物需要对多种外部刺激作出反应。尽管已经进行了广泛的研究以研究烟曲霉中的细胞内信号转导,但是对于特异性刺激和激活这些信号级联的相应受体知之甚少。在这里,两个假定的G蛋白偶联受体,GprC和GprD,就其细胞功能进行了表征。删除相应的基因会导致严重的生长缺陷,因为菌丝的延伸减少,发芽受到抑制,菌丝的分支水平升高。发现生长缺陷与温度有关。温度越高,生长缺陷越明显。此外,与野生型相比,突变株对由活性氧中间体引起的环境胁迫的敏感性增加,并且突变株在鼠感染模型中显示出毒力减弱。两种突变体,尤其是ΔgprC菌株,都显示出对环孢霉素(钙调神经磷酸酶信号转导通路的抑制剂)的耐受性增加。转录组分析表明,在gprC和gprD缺失突变体中,初级代谢基因的转录本较少,而几个次级代谢基因簇的转录上调。综上所述,我们的数据表明受体通过钙调神经磷酸酶途径的调节参与整合和处理应激信号。

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