Host-derived reactive oxygen species trigger activation of the Candida albicans transcription regulator Rtg1/3.
Host-derived reactive oxygen species trigger activation of the Candida albicans transcription regulator Rtg1/3.
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DOI：
10.1371/journal.ppat.1011692
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发表时间：
2023-09
期刊：
影响因子：
6.7
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中科院分区：
文献类型：
--
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指示哺乳动物宿主环境并指示激活与人类相关的微生物中的信号通路的信号通常是未知的。人类真菌病原菌白色念珠菌中的转录调控因子Rtg1/3是决定宿主定植和致病性的关键因素。Rtg1/3‘S的活性在一定程度上是通过在真菌的细胞质和细胞核之间穿梭调节因子来控制的。然而，Rtg1/3对宿主信号(S)的反应(S)仍不清楚。在这里，我们报告了中性粒细胞衍生的活性氧物种(ROS)指导了这种白色念珠菌转录调节因子的亚细胞定位。当人或鼠的中性粒细胞吞噬念珠菌细胞时，调节器穿梭到真菌的细胞核。利用遗传和化学方法破坏中性粒细胞的氧化爆发，我们证实了由NOX2复合体产生的氧化剂-而不是由髓过氧化物酶产生的氧化剂-触发Rtg1/3‘S向核迁移。此外，我们筛选了一组白色念珠菌激酶缺失突变体，我们发现MKC1信号通路参与了该真菌对Rtg1/3的ROS依赖性调控。最后，我们发现Rtg1/3以ROS依赖的方式促进白色念珠菌对线虫的毒力，因为rtg1和rtg3突变体在野生型线虫中显示出毒力缺陷，而在ROS缺乏的线虫中不显示。我们的发现确立了NOX2衍生的ROS是指导多效性真菌调节因子Rtg1/3活性的关键信号。白色念珠菌是人类普遍存在的一种真菌。它存在于人体的不同部位，包括口腔和胃肠道。白念珠菌也是威胁生命的传播性感染的主要原因。与其他与人类相关的微生物一样，这种真菌在宿主组织中感受到的信号的确切性质通常是未知的。我们已经确定，白色念珠菌调控系统Rtg1/3对于真菌在哺乳动物宿主内的定植和增殖是至关重要的，这意味着该调控因子的活性可能会对一个或多个指示宿主环境的信号做出反应。在这项研究中，我们试图确定指导调节因子在宿主内部活动的信号分子(S)和信号分子。我们报道，宿主衍生的活性氧物种通过促进该调节器从细胞质到真菌细胞核的转位来决定该调节器的激活。作为决定Rtg1/3活性的信号，由于Rtg1/3构成了一个相当大的调控网络的中心节点，驱动哺乳动物宿主的定植，因此Rtg1/3可能伴随着激活念珠菌在宿主中生存所需的额外途径。
The signals that denote mammalian host environments and dictate the activation of signaling pathways in human-associated microorganisms are often unknown. The transcription regulator Rtg1/3 in the human fungal pathogen Candida albicans is a crucial determinant of host colonization and pathogenicity. Rtg1/3’s activity is controlled, in part, by shuttling the regulator between the cytoplasm and nucleus of the fungus. The host signal(s) that Rtg1/3 respond(s) to, however, have remained unclear. Here we report that neutrophil-derived reactive oxygen species (ROS) direct the subcellular localization of this C. albicans transcription regulator. Upon engulfment of Candida cells by human or mouse neutrophils, the regulator shuttles to the fungal nucleus. Using genetic and chemical approaches to disrupt the neutrophils’ oxidative burst, we establish that the oxidants produced by the NOX2 complex–but not the oxidants generated by myeloperoxidase–trigger Rtg1/3’s migration to the nucleus. Furthermore, screening a collection of C. albicans kinase deletion mutants, we implicate the MKC1 signaling pathway in the ROS-dependent regulation of Rtg1/3 in this fungus. Finally, we show that Rtg1/3 contributes to C. albicans virulence in the nematode Caenorhabditis elegans in an ROS-dependent manner as the rtg1 and rtg3 mutants display virulence defects in wild-type but not in ROS deficient worms. Our findings establish NOX2-derived ROS as a key signal that directs the activity of the pleiotropic fungal regulator Rtg1/3. Candida albicans is a ubiquitous fungus of humans. It inhabits various compartments of the human body including oral cavity and gastrointestinal tract. C. albicans is also a leading cause of life-threatening disseminated infections. As with other human-associated microorganisms, the exact nature of the signals sensed by this fungus inside host tissues is often unknown. We have established that the C. albicans regulatory system Rtg1/3 is pivotal for the fungus to colonize and proliferate inside the mammalian host, implying that the regulator’s activity may respond to one or more cues that denote the host environment. In this study, we sought to pinpoint the cue(s) and signaling molecules that direct the regulator’s activity inside the host. We report that host-derived reactive oxygen species determine the activation of this regulator by promoting its translocation from the cytoplasm to the nucleus of the fungus. As a signal that dictates the activity of Rtg1/3, reactive oxygen species may concomitantly direct the activation of additional pathways required for Candida to endure in the host because Rtg1/3 constitutes a central node of a rather large regulatory network driving mammalian host colonization.
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