Genetic studies have revealed critical roles of transcription factor Pdr1 and the Mediator subunit Gal11A in regulating azole resistance in Candida glabrata. Recently, PDR1 gain-of-function (GOF) mutations have been shown to not only increase azole resistance but also enhance adherence during C. glabrata infection. However, mechanism of how Pdr1 regulates adherence, especially the implication of PDR1 GOF mutations in the regulation of the major adhesin gene EPA1, remains uncharacterized. Initially, we unexpectedly observed that expression of PDR1 harbouring GOF mutation G346D down-regulated EPA1 transcription and attenuated adherence to epithelial cells in different strain backgrounds. Given that PDR1 GOF mutations have been previously regarded as stimulators for adherence of this species, these findings prompted us to explore the regulation of EPA1 by wild-type Pdr1 and Pdr1 harbouring G346D mutation. Epitope tagged version of Pdr1 and Gal11A were utilized to determine the association of Pdr1 and Gal11A with EPA1 promoter. A combination of approaches including deletion, molecular, and biochemical assays showed that EPA1 is a direct target of Pdr1, and demonstrated for the first time that PDR1 G346D mutation decreases EPA1 expression and attenuates adherence to epithelial cells via enhancing recruitment of Gal11A. Taken together, our data propose a critical role of Gal11A in Pdr1-regulated EPA1 expression and adherence to epithelial cells, which could be utilized a novel therapeutic target for the treatment of hyper-adherent C. glabrata infection.

遗传学研究揭示了转录因子Pdr1和介体亚基Gal11A在调节光滑念珠菌中对唑的抗性中的关键作用。最近，已显示PDR1功能获得（GOF）突变不仅增加了对唑的抗性，而且还增强了光滑小球藻感染期间的依从性。然而，Pdr1如何调节粘附，尤其是主要粘附素基因EPA1的调节中PDR1 GOF突变的含义的机制仍然未知。最初，我们意外地观察到带有GOF突变G346D的PDR1的表达下调了EPA1转录和在不同菌株背景下对上皮细胞的粘附减弱。鉴于先前已将PDR1 GOF突变视为该物种粘附的刺激物，因此这些发现促使我们探索野生型Pdr1和具有G346D突变的Pdr1对EPA1的调控。利用Pdr1和Gal11A的表位标记版本来确定Pdr1和Gal11A与EPA1启动子的关联。包括缺失，分子和生化分析在内的多种方法的组合表明EPA1是Pdr1的直接靶标，并首次证明PDR1 G346D突变降低了EPA1表达并通过增强Gal11A的募集减弱对上皮细胞的粘附。综上所述，我们的数据提出了Gal11A在Pdr1调控的EPA1表达和对上皮细胞的粘附中的关键作用，可将其用作治疗高粘附性光滑毛囊梭菌感染的新型治疗靶标。