Candida glabrata Yap6 Recruits Med2 To Alter Glycerophospholipid Composition and Develop Acid pH Stress Resistance

Abstract

<i>Candida glabrata</i> is a high-performance microbial cell factory for the production of organic acids. To elucidate the role of the <i>C. glabrata</i> Mediator tail subunit Med2 (<i>Cg</i>Med2) at pH 2.0, we deleted or overexpressed <i>Cg</i>Med2 and used transcriptome analysis to identify genes that are regulated by <i>Cg</i>Med2. At pH 2.0, the deletion of <i>Cg</i>Med2 resulted in a cell growth decrease of 26.1% and a survival decrease of 32.3%. Overexpression of <i>Cg</i>Med2 increased cell growth by 12.4% and cell survival by 5.9% compared to the wild-type strain. Transcriptome and phenotypic analyses identified <i>Cg</i>Yap6 as a transcription factor involved in acid pH stress tolerance. Deletion of <i>Cg</i>Yap6 caused growth defects, whereas its overexpression enhanced cell growth at pH 2.0. Furthermore, total glycerophospholipid content and membrane integrity decreased by 33.4% and 21.8%, respectively, in the <i>Cg</i>Med2Δ strain; however, overexpression of <i>Cg</i>Med2 increased the total glycerophospholipid content and membrane integrity by 24.7% and 12.1%, respectively, compared with those of the wild-type strain at pH 2.0. These results demonstrated that under acid pH stress, <i>Cg</i>Med2 physically interacts with <i>Cg</i>Yap6, which translocates from the cytoplasm to the nucleus after being phosphorylated by the protein kinase <i>Cg</i>Yak1. Once in the nucleus, <i>Cg</i>Yap6 recruits <i>Cg</i>Med2 to express glycerophospholipid-related genes. Our study elucidated the function of <i>Cg</i>Med2 under acid pH stress and provides a potential strategy to equip <i>Candida glabrata</i> with low-pH resistance during organic acid fermentation.<b>IMPORTANCE</b> This study investigated the function of the Mediator tail subunit <i>Cg</i>Med2 in <i>C. glabrata</i> under low-pH stress. The protein kinase <i>Cg</i>Yak1 activates <i>Cg</i>Yap6 for the recruitment of <i>Cg</i>Med2, which in turn increases glycerophospholipid content and membrane integrity to confer low-pH stress tolerance. This study establishes a new link between the Mediator tail subunit and transcription factors. Overall, these findings indicate that <i>Cg</i>Med2 is a novel target to induce the low-pH stress response in <i>C. glabrata</i>.