SAGA/ADA Complex Subunit Ada2 Is Required for Cap1-but Not Mrr1-Mediated Upregulation of the Candida albicans Multidrug Efflux Pump MDR1
SAGA/ADA Complex Subunit Ada2 Is Required for Cap1-but Not Mrr1-Mediated Upregulation of the Candida albicans Multidrug Efflux Pump MDR1
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DOI：
10.1128/aac.03065-14
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发表时间：
2014-09-01
影响因子：
4.9
通讯作者：
Morschhauser, Joachim
中科院分区：
文献类型：
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作者：
Ramirez-Zavala, Bernardo;Mogavero, Selene;Morschhauser, Joachim
多药外排泵mdr1的过度表达是致病酵母菌对抗真菌药物氟康唑产生耐药性的机制之一。在对氟康唑耐药的临床分离株中，mdr1的结构性上调是由锌簇转录因子mr1的功能获得突变引起的。已有研究表明，MRr1通过招募SAGA/ADA共激活复合体的亚单位Ada2来激活mdr1转录。然而，mdr1的表达也受到bZIP转录因子Cap1的调节，该转录因子介导了白色念珠菌的氧化应激反应。在这里，我们证明了含有功能增益突变的高活性MRr1独立于Ada2促进MDR1的过度表达。相反，C末端截短的高活性Cap1在野生型菌株中导致MDR1过度表达，但在缺乏ADA2的突变体中仅微弱表达。在苯菌素或过氧化氢的存在下，以mrr1和cap1依赖的方式诱导mdr1表达的化合物在野生型和ada2 Delta细胞中以相同的效率上调mdr1。这些结果表明，Cap1，而不是MRr1，将Ada2招募到mdr1启动子来诱导这种多药外排泵的表达，并且在含有mrr1功能获得突变的氟康唑耐药白色念珠菌中，Ada2不是mdr1高表达所必需的。
Overexpression of the multidrug efflux pump MDR1 is one mechanism by which the pathogenic yeast Candida albicans develops resistance to the antifungal drug fluconazole. The constitutive upregulation of MDR1 in fluconazole-resistant, clinical C. albicans isolates is caused by gain-of-function mutations in the zinc cluster transcription factor Mrr1. It has been suggested that Mrr1 activates MDR1 transcription by recruiting Ada2, a subunit of the SAGA/ADA coactivator complex. However, MDR1 expression is also regulated by the bZIP transcription factor Cap1, which mediates the oxidative stress response in C. albicans. Here, we show that a hyperactive Mrr1 containing a gain-of-function mutation promotes MDR1 overexpression independently of Ada2. In contrast, a C-terminally truncated, hyperactive Cap1 caused MDR1 overexpression in a wild-type strain but only weakly in mutants lacking ADA2. In the presence of benomyl or H2O2, compounds that induce MDR1 expression in an Mrr1- and Cap1-dependent fashion, MDR1 was upregulated with the same efficiency in wild-type and ada2 Delta cells. These results indicate that Cap1, but not Mrr1, recruits Ada2 to the MDR1 promoter to induce the expression of this multidrug efflux pump and that Ada2 is not required for MDR1 overexpression in fluconazole-resistant C. albicans strains containing gain-of-function mutations in Mrr1.