Divergent functions of three Candida albicans zinc-cluster transcription factors (CTA4, ASG1 and CTF1) complementing pleiotropic drug resistance in Saccharomyces cerevisiae
Divergent functions of three Candida albicans zinc-cluster transcription factors (CTA4, ASG1 and CTF1) complementing pleiotropic drug resistance in Saccharomyces cerevisiae
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DOI：
10.1099/mic.0.2007/016063-0
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发表时间：
2008-05-01
期刊：
影响因子：
2.8
通讯作者：
Sanglard, Dominique
中科院分区：
文献类型：
--
作者：
Coste, Alix T.;Ramsdale, Mark;Sanglard, Dominique
abc转运基因PDR5是酿酒酵母多效耐药的介导因子之一。该基因受至少两个具有Zn(2)-Cys(6)指dna结合基序的转录因子Pdr1p和Pdr3p调控。在这项工作中，我们在白色念珠菌中寻找这些转录因子的功能同源物。从酿酒葡萄球菌PDR1和PDR3缺失突变体中筛选出白色念珠菌基因文库，并分离出抗唑类抗真菌药的克隆。从这些无性系中鉴定出3个抗唑基因。这些基因（CTA4、ASG1和CTF1）在其n端结构域编码含有Zn(2)-Cys(6)型锌指基序的蛋白。酿酒酵母中表达的白色念珠菌基因可以激活PDR5-lacZ报告系统的转录，该报告系统的活性依赖于pdr5。它们也可能使缺乏PDR1、PDR3和PDR5的酿酒葡萄球菌菌株对唑类药物产生耐药性，这表明CTA4-、ASG1-和ctf1依赖性的唑类药物耐药性可能是由酿酒葡萄球菌中PDR5以外的基因引起的。白色念珠菌中CTA4、ASG1和CTF1的缺失对氟康唑敏感性没有影响，也没有改变abc转运基因CDR1和CDR2或主要促进基因MDR1的表达，这些基因编码多药转运体，被称为白色念珠菌耐药的介质。然而，对白色念珠菌突变体的额外表型筛选试验显示，ASG1的存在对于维持非发酵碳源（醋酸钠、乙酸、乙醇）上的生长是必要的。结论：白色念珠菌具有酿酒葡萄球菌pdr1p和Pdr3p转录因子的功能同源物；然而，它们在白色念珠菌中的特性已经被重新连接到其他功能上。
One of the mediators of pleiotropic drug resistance in Saccharomyces cerevisiae is the ABC-transporter gene PDR5. This gene is regulated by at least two transcription factors with Zn(2)-Cys(6) finger DNA-binding motifs, Pdr1p and Pdr3p. In this work, we searched for functional homologues of these transcription factors in Candida albicans. A C. albicans gene library was screened in a S. cerevisiae mutant lacking PDR1 and PDR3 and clones resistant to azole antifungals were isolated. From these clones, three genes responsible for azole resistance were identified. These genes (CTA4, ASG1 and CTF1) encode proteins with Zn(2)-Cys(6)-type zinc finger motifs in their N-terminal domains. The C. albicans genes expressed in S. cerevisiae could activate the transcription of a PDR5-lacZ reporter system and this reporter activity was PDRE-dependent. They could also confer resistance to azoles in a S. cerevisiae strain lacking PDR1, PDR3 and PDR5, suggesting that CTA4-, ASG1- and CTF1-dependent azole resistance can be caused by genes other than PDR5 in S. cerevisiae. Deletion of CTA4, ASG1 and CTF1 in C. albicans had no effect on fluconazole susceptibility and did not alter the expression of the ABC-transporter genes CDR1 and CDR2 or the major facilitator gene MDR1, which encode multidrug transporters known as mediators of azole resistance in C. albicans. However, additional phenotypic screening tests on the C. albicans mutants revealed that the presence of ASG1 was necessary to sustain growth on non-fermentative carbon sources (sodium acetate, acetic acid, ethanol). In conclusion, C. albicans possesses functional homologues of the S. cerevisiae Pdr1 p and Pdr3p transcription factors; however, their properties in C. albicans have been rewired to other functions.