Okagaki Laura H, Wang Yina, Ballou Elizabeth R, O'Meara Teresa R, Bahn Yong-Sun, Alspaugh J Andrew, Xue Chaoyang, Nielsen Kirsten
Department of Microbiology, University of Minnesota, Minneapolis, MN, USA.
Eukaryot Cell. 2011 Oct;10(10):1306-16. doi: 10.1128/EC.05179-11. Epub 2011 Aug 5.
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.
巨细胞是最近描述的新型隐球菌致病真菌的一种形态形式。在肺部感染的最早阶段出现，巨细胞比正常酵母样细胞大5到10倍，从而抵抗肺吞噬细胞的吞噬并有利于感染的持续存在。这些增大的细胞表现出改变的荚膜结构、增厚的细胞壁、增加的倍性以及对亚硝化和氧化应激的抗性。我们证明，两种G蛋白偶联受体对巨细胞表型的诱导很重要：Ste3a信息素受体（在a交配型细胞中）和Gpr5蛋白。这两种受体都通过环磷酸腺苷（cAMP）/蛋白激酶A（PKA）途径的元件控制巨细胞的形成。反过来，这种保守的信号通路通过PKA调节的Rim101转录因子介导其对巨细胞的作用。巨细胞形成所需的其他下游效应器包括G(1)细胞周期蛋白Pcl103、Rho104 GTP酶以及两种GTP酶激活蛋白Gap1和Cnc1560。这些观察结果支持了正在发展的模型，即PKA信号通路在多种人类病原体中协调调节许多与毒力相关的表型。
