Cryptococcal Titan Cell Formation Is Regulated by G-Protein Signaling in Response to Multiple Stimuli
Cryptococcal Titan Cell Formation Is Regulated by G-Protein Signaling in Response to Multiple Stimuli
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DOI：
10.1128/ec.05179-11
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发表时间：
2011-10-01
期刊：
影响因子：
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通讯作者：
Nielsen, Kirsten
中科院分区：
文献类型：
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作者：
Okagaki, Laura H.;Wang, Yina;Nielsen, Kirsten
泰坦细胞是新近描述的致病真菌新生隐球菌的一种形态。在肺部感染的早期阶段，泰坦细胞比正常的酵母样细胞大5到10倍，从而抵抗肺吞噬细胞的吞噬，有利于感染的持久性。这些扩大的细胞表现出被膜结构改变，细胞壁增厚，倍性增加，并对亚硝化和氧化应激具有抵抗力。我们证明了两个G蛋白偶联受体对于泰坦细胞表型的诱导是重要的：Ste3a信息素受体(在交配型a细胞中)和Gpr5蛋白。这两种受体都通过环磷酸腺苷(CAMP)/蛋白激酶A(PKA)途径的元件控制泰坦细胞的形成。这一保守的信号通路反过来通过PKA调节的Rim101转录因子介导其对TITAN细胞的影响。泰坦细胞形成所需的其他下游效应因子包括G(1)细胞周期蛋白Pcl103、Rho104 GTP酶和两个GTP酶激活蛋白Gap1和Cnc1560。这些观察结果支持发展模型，在该模型中，PKA信号通路协调调节不同人类病原体的许多毒力相关表型。
The titan cell is a recently described morphological form of the pathogenic fungus Cryptococcus neoformans. Occurring during the earliest stages of lung infection, titan cells are 5 to 10 times larger than the normal yeast-like cells, thereby resisting engulfment by lung phagocytes and favoring the persistence of infection. These enlarged cells exhibit an altered capsule structure, a thickened cell wall, increased ploidy, and resistance to nitrosative and oxidative stresses. We demonstrate that two G-protein-coupled receptors are important for induction of the titan cell phenotype: the Ste3a pheromone receptor (in mating type a cells) and the Gpr5 protein. Both receptors control titan cell formation through elements of the cyclic AMP (cAMP)/protein kinase A (PKA) pathway. This conserved signaling pathway, in turn, mediates its effect on titan cells through the PKA-regulated Rim101 transcription factor. Additional downstream effectors required for titan cell formation include the G(1) cyclin Pcl103, the Rho104 GTPase, and two GTPase-activating proteins, Gap1 and Cnc1560. These observations support developing models in which the PKA signaling pathway coordinately regulates many virulence-associated phenotypes in diverse human pathogens.