Ras links cellular morphogenesis to virulence by regulation of the MAP kinase and cAMP signalling pathways in the pathogenic fungus Candida albicans
Ras links cellular morphogenesis to virulence by regulation of the MAP kinase and cAMP signalling pathways in the pathogenic fungus Candida albicans
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DOI：
10.1046/j.1365-2958.2001.02672.x
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发表时间：
2001-11-01
影响因子：
3.6
通讯作者：
Schröppel, K
中科院分区：
文献类型：
--
作者：
Leberer, E;Harcus, D;Schröppel, K
致病真菌白色念珠菌能够响应各种各样的环境线索，其形态从出芽酵母转变为极化丝状形式。我们证明C.白色念珠菌CaRas 1 p是这种形态转变所必需的，从而有助于致病性的发展。然而，CaRas 1 p不是细胞活力所必需的。CaRAS 1基因的两个等位基因的缺失导致在形态学转变中的体外缺陷，通过补充具有cAMP的生长培养基或过表达诱导有丝分裂原活化蛋白（MAP）激酶级联的组分来逆转。在突变体细胞中，SAP 4 -6基因编码的特异性分泌型β-淀粉酰蛋白酶的诱导被阻断。在吞噬C.在巨噬细胞培养试验中，以及在全身性念珠菌病小鼠模型中，在肾脏感染后，在体内观察白色念珠菌细胞。在巨噬细胞测定中，突变细胞对吞噬作用的抵抗力较低。此外，细丝形成的缺陷与小鼠模型中毒力的降低有关。这些结果表明，在响应环境的线索，CaRas 1 p是必需的MAP激酶信号通路和cAMP信号通路的调节。CaRas 1 p依赖的这些通路的激活有助于C.白念珠菌细胞通过诱导极化形态发生。这些发现阐明了一个新的医学相关的作用，Ras在细胞形态和毒力的一个重要的人类传染病。
The pathogenic fungus Candida albicans is capable of responding to a wide variety of environmental cues with a morphological transition from a budding yeast to a polarized filamentous form. We demonstrate that the Ras homologue of C. albicans, CaRas1p, is required for this morphological transition and thereby contributes to the development of pathogenicity. However, CaRas1p is not required for cellular viability. Deletion of both alleles of the CaRAS1 gene caused in vitro defects in morphological transition that were reversed by either supplementing the growth media with cAMP or overexpressing components of the filament-inducing mitogen-activated protein (MAP) kinase cascade. The induction of filament-specific secreted aspartyl proteinases encoded by the SAP4-6 genes was blocked in the mutant cells. The defects in filament formation were also observed in situ after phagocytosis of C. albicans cells in a macrophage cell culture assay and, in vivo, after infection of kidneys in a mouse model for systemic candidiasis. In the macrophage assay, the mutant cells were less resistant to phagocytosis. Moreover, the defects in filament formation were associated with reduced virulence in the mouse model. These results indicate that, in response to environmental cues, CaRas1p is required for the regulation of both a MAP kinase signalling pathway and a cAMP signalling pathway. CaRas1p-dependent activation of these pathways contributes to the pathogenicity of C. albicans cells through the induction of polarized morphogenesis. These findings elucidate a new medically relevant role for Ras in cellular morphogenesis and virulence in an important human infectious disease.