Interaction of Cryptococcus neoformans Rim101 and protein kinase A regulates capsule.
Interaction of Cryptococcus neoformans Rim101 and protein kinase A regulates capsule.
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DOI：
10.1371/journal.ppat.1000776
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发表时间：
2010-02-19
期刊：
影响因子：
6.7
通讯作者：
Alspaugh JA
中科院分区：
文献类型：
--
作者：
O'Meara TR;Norton D;Price MS;Hay C;Clements MF;Nichols CB;Alspaugh JA
新型隐球菌是一种流行的人类真菌病原体，必须在各种组织中生存，以建立人类感染。我们已经确定了C。Rim 101转录因子是许多真菌物种中高度保守的pH反应调节因子。rim 101 Δ突变菌株在碱性pH、盐浓度增加和铁限制的存在下显示出与其他真菌物种相似的生长缺陷。然而，rim 101 Δ菌株的特征还在于荚膜中的显著缺陷，这是一种重要的毒力相关表型。这种荚膜缺陷可能是由于多糖附着在细胞表面的改变，而不是多糖生物合成的改变。与许多其他C。在新型隐球菌荚膜缺陷型菌株中，rim 101 Δ突变体在隐球菌病的动物模型中是高毒力的。然而，在其他真菌物种中，Rim 101的激活是通过保守的Rim途径发生的，我们证明了C。新生儿Rim 101也被cAMP/PKA途径激活。我们在这里报告说，C。新生儿使用PKA和Rim途径来调节Rim 101转录因子的定位、激活和加工。我们还证明了特定的主机相关的激活条件下Rim 101切割，表明C。新形式原虫已经增选保守的信号传导途径来响应受感染宿主内的特定生态位。这些结果建立了一个新的机制Rim 101激活和整合两个保守的信号级联反应的主机环境条件。 新型隐球菌是一种环境真菌和机会致病菌。这种真菌在人类宿主中的存活取决于其感知宿主环境并以保护性细胞变化做出反应的能力。已知cAMP/PKA信号转导级联对于感知宿主特异性环境和调节细胞适应（如被膜和增加的铁摄取）是重要的，所述细胞适应是感染宿主内生长所必需的。在这里，我们的文件，不像在其他真菌物种，C。Rim 101同源物直接受PKA调控。Rim 101信号通路也参与荚膜调节和毒力。我们的研究表明，Rim 101整合了两个保守的信号转导级联，它是重要的微生物致病调节。
Cryptococcus neoformans is a prevalent human fungal pathogen that must survive within various tissues in order to establish a human infection. We have identified the C. neoformans Rim101 transcription factor, a highly conserved pH-response regulator in many fungal species. The rim101Δ mutant strain displays growth defects similar to other fungal species in the presence of alkaline pH, increased salt concentrations, and iron limitation. However, the rim101Δ strain is also characterized by a striking defect in capsule, an important virulence-associated phenotype. This capsular defect is likely due to alterations in polysaccharide attachment to the cell surface, not in polysaccharide biosynthesis. In contrast to many other C. neoformans capsule-defective strains, the rim101Δ mutant is hypervirulent in animal models of cryptococcosis. Whereas Rim101 activation in other fungal species occurs through the conserved Rim pathway, we demonstrate that C. neoformans Rim101 is also activated by the cAMP/PKA pathway. We report here that C. neoformans uses PKA and the Rim pathway to regulate the localization, activation, and processing of the Rim101 transcription factor. We also demonstrate specific host-relevant activating conditions for Rim101 cleavage, showing that C. neoformans has co-opted conserved signaling pathways to respond to the specific niche within the infected host. These results establish a novel mechanism for Rim101 activation and the integration of two conserved signaling cascades in response to host environmental conditions. Cryptococcus neoformans is an environmental fungus and an opportunistic human pathogen. Survival of this fungus within a human host depends on its ability to sense the host environment and respond with protective cellular changes. It is known that the cAMP/PKA signal transduction cascade is important for sensing host-specific environments and regulating the cellular adaptations, such as capsule and increased iron uptake, that are necessary for growth inside the infected host. Here we document that, unlike what has been described in other fungal species, a C. neoformans Rim101 homologue is directly regulated by PKA. The Rim101 signaling pathway is also involved in capsule regulation and virulence. Our study demonstrates that Rim101 integrates two conserved signal transduction cascades, and it is important in regulating microbial pathogenesis.
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