Sequence modification of the master regulator Pdr1 interferes with its transcriptional autoregulation and confers altered azole resistance in Candida glabrata
Sequence modification of the master regulator Pdr1 interferes with its transcriptional autoregulation and confers altered azole resistance in Candida glabrata
复制标题
主调控因子 Pdr1 的序列修饰干扰其转录自动调节并赋予光滑念珠菌的唑类抗性改变
DOI：
10.1093/femsyr/foy038
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发表时间：
2018
影响因子：
3.2
通讯作者：
Chen Changbin
中科院分区：
文献类型：
--
作者：
Tian Yuan;Gao Ning;Ni Qi;Mao Yinhe;Dong Danfeng;Huang Xinhua;Jiang Cen;Li Zhen;Zhang Lihua;Wang Xuefeng;Peng Yibing;Chen Changbin
转录调控因子Pdr1在光滑念珠菌对唑类药物耐药性的调控中起着积极的作用。先前的研究表明，Pdr1的羧基(C)末端序列在完成其功能中的重要性，因为该区域介导了Pdr1与共激活因子Gal11A之间的相互作用，并对Pdr1靶标的激活至关重要。然而，Pdr1的调控机制，特别是其C末端在调控活动中的作用，仍不是很清楚。在这项研究中，我们意外地观察到，在一株具有单一GOF突变的唑类耐药临床分离株中，Pdr1的C端修饰导致了Pdr1表达水平下降、Pdr1靶点下调和唑类过敏等不良反应。重要的是，C-末端3×10标记显著降低了Pdr1与其自身启动子中的多效性药物反应元件的结合，促进了不规则的细胞错误定位，从而扰乱了这一主调控因子的转录自动调节。出乎意料的是，这种异常的细胞质定位导致了与参与耐药的辅助激活因子Gal11A的非功能性相互作用。基于这些发现，我们认为Pdr1的C末端序列对其稳定性和功能至关重要，对该区域的靶向调控可能是未来对抗C的一种有前途的策略。无菌感染与耐药。
The transcriptional regulator Pdr1 plays a positive role in regulating azole drug resistance inCandida glabrata. Previous studies have shown the importance of the carboxyl (C)-terminal sequence of Pdr1 in fulfilling its function, as this region mediates interactions between Pdr1 and the co-activator Gal11A and is crucial for activation of Pdr1 targets. However, mechanisms of how Pdr1 is regulated, especially implication of its C-terminus in the regulatory activity, remain uncharacterized. In this study, we unexpectedly observed that the C-terminal modification of Pdr1 in an azole-resistant clinical isolate harboring a single GOF mutation, resulted in adverse effects such as decreased expression levels of Pdr1, downregulation of Pdr1 targets and azole hypersensitivity. Importantly, the C-terminal 3 × FLAG tagging significantly decreased the binding of Pdr1 to the pleiotropic drug response elements in its own promoter, promoted an irregular cellular mislocalization and thereby disrupted the transcriptional autoregulation of this master regulator. Unexpectedly, the aberrant cytoplasmic localization caused a non-functional interaction with Gal11A, a co-activator involved in drug resistance. Based on these findings, we proposed that C-terminal sequence of Pdr1 is vital for its stability and functionality, and targeting regulation of this region may represent a promising future strategy for combatingC. glabratainfection and drug resistance.