Bypass of Candida albicans Filamentation/Biofilm Regulators through Diminished Expression of Protein Kinase Cak1.
Bypass of Candida albicans Filamentation/Biofilm Regulators through Diminished Expression of Protein Kinase Cak1.
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DOI：
10.1371/journal.pgen.1006487
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发表时间：
2016-12
期刊：
影响因子：
4.5
通讯作者：
Mitchell AP
中科院分区：
文献类型：
--
作者：
Woolford CA;Lagree K;Xu W;Aleynikov T;Adhikari H;Sanchez H;Cullen PJ;Lanni F;Andes DR;Mitchell AP
植入型医疗器械上生物膜的形成是白色念珠菌致死性侵袭性感染的主要来源。这种真菌的丝状生长与生物膜的形成有关，因为许多与丝状化相关的基因是表面附着所必需的。细胞周期或细胞生长缺陷可以诱导丝状化，但我们对细胞周期/细胞生长抑制后丝状化与丝状化相关基因表达之间的偶联的信息有限。在这里，我们通过筛选与细胞周期/细胞生长控制有关的蛋白激酶相关基因表达减弱的突变，确定CDK激活蛋白激酶Cak1是丝化和丝化相关基因表达的决定因素。Cak1缺失表达(DX)菌株在缺乏典型诱导信号的情况下表现出丝状生长并表达丝状相关基因。在野生型背景下，丝化相关基因的表达取决于转录因子Bcr1、BRG1、Efg1、Tec1和Ume6。在Cak1 DX背景下，丝化相关基因表达对每个转录因子的依赖基本上得到了缓解。丝化相关基因表达激活子的意外旁路具有功能后果，即在缺少Bcr1、BRG1、Tec1、Ume6或同时缺少BRG1和Ume6的情况下，能够形成生物膜。在没有Efg1的情况下，它也可以使丝状细胞形态发生，但不能形成生物膜。由于已知这些转录因子具有共同的靶基因，我们认为细胞周期/细胞生长限制导致几个转录因子的激活，从而减少对任何一个的依赖。病原体白色念珠菌作为生物膜生长在表面的能力是感染能力的决定因素，因为植入的医疗器械上的生物膜会感染种子。这种生物形成生物膜需要丝状细胞的生长和丝化相关基因的表达。抑制细胞增殖可以诱导丝状细胞的形成，就像我们在这里发现的那样，表达细胞周期调节因子Cak1水平大大降低的菌株。令人惊讶的是，当Cak1水平降低时，生物膜的形成不依赖于许多中央生物膜调控基因。这种对增殖抑制的反应可能反映了许多生物膜调节因子的激活，从而减轻了对任何一个调节因子的依赖。通过抑制增殖促进生物被膜的形成，这也是许多细菌病原体的特性，可能是抗菌剂对生物被膜的有限效果的原因。
Biofilm formation on implanted medical devices is a major source of lethal invasive infection by Candida albicans. Filamentous growth of this fungus is tied to biofilm formation because many filamentation-associated genes are required for surface adherence. Cell cycle or cell growth defects can induce filamentation, but we have limited information about the coupling between filamentation and filamentation-associated gene expression after cell cycle/cell growth inhibition. Here we identified the CDK activating protein kinase Cak1 as a determinant of filamentation and filamentation-associated gene expression through a screen of mutations that diminish expression of protein kinase-related genes implicated in cell cycle/cell growth control. A cak1 diminished expression (DX) strain displays filamentous growth and expresses filamentation-associated genes in the absence of typical inducing signals. In a wild-type background, expression of filamentation-associated genes depends upon the transcription factors Bcr1, Brg1, Efg1, Tec1, and Ume6. In the cak1 DX background, the dependence of filamentation-associated gene expression on each transcription factor is substantially relieved. The unexpected bypass of filamentation-associated gene expression activators has the functional consequence of enabling biofilm formation in the absence of Bcr1, Brg1, Tec1, Ume6, or in the absence of both Brg1 and Ume6. It also enables filamentous cell morphogenesis, though not biofilm formation, in the absence of Efg1. Because these transcription factors are known to have shared target genes, we suggest that cell cycle/cell growth limitation leads to activation of several transcription factors, thus relieving dependence on any one. The ability of the pathogen Candida albicans to grow on surfaces as biofilms is a determinant of infection ability, because biofilms on implanted medical devices seed infections. Biofilm formation by this organism requires growth in the form of filamentous cells and the expression of filamentation-associated genes. Inhibition of cell proliferation can induce filamentous cell formation, as we find here for strains that express greatly reduced levels of the cell cycle regulator Cak1. Surprisingly, biofilm formation occurs independently of many central biofilm regulatory genes when Cak1 levels are reduced. This response to proliferation inhibition may reflect the activation of numerous biofilm regulators, thus relieving the dependence on any one regulator. The stimulation of biofilm formation by proliferation inhibition, a property of many bacterial pathogens as well, may contribute to the limited effectiveness of antimicrobials against biofilms.
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