Regulation of endoplasmic reticulum stress resistance in yeast

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In eukaryotic cells, nearly one third of all newly synthetized proteins enter the endoplasmic reticulum (ER), an organelle containing specialized quality control machinery that ensures the proper folding of the nascent peptides. Failure to fold into their proper conformation leads to loss of protein function and cell death. Thus, cells have evolved signaling pathways that respond to sudden increases in the ER misfolded protein burden (ER stress) caused by various factors such as genetic mutations or environmental insults. In response to ER stress, cells activate the unfolded protein response (UPR). This evolutionarily conserved coping mechanism increases the expression of genes encoding proteins that help restore ER homeostasis by improving protein folding and misfolded protein degradation. Recently, it has emerged that the UPR can not only be activated by misfolded proteins, but also by changes in the lipid composition of the ER membrane. The biological relevance of this differential activation remains elusive. The mechanisms of ER stress resolution and UPR have been extensively characterized using the budding yeast Saccharomyces cerevisiae, which allows rapid and extensive genetic manipulations. However, the role of the UPR is other yeast species such as the pathogen Candida albicans remains poorly understood. Interestingly, C. albicans cells with compromised UPR display hypersensitivity to antifungal drugs and reduced pathogenicity. Using a combination of studies in both S. cerevisiae and C. albicans, I propose to investigate how the UPR control gene expression associated with the antifungal response and pathogenicity. My central hypothesis is that the different mode of UPR activation deploys a specific transcriptional program that adapt the ER folding environment to regulate antifungal resistance and pathogenicity. The long-term goal of my research program is to identify the underlying mechanisms that control UPR-driven antifungal resistance and pathogenicity. Specifically, my short-term objectives are to: (1) Elucidate how the ER stress sensor Ire1 is activated by antifungal drugs. (2) Define the C. albicans UPR. (3) Characterize the role of UPR target genes in C. albicans antifungal resistance and pathogenicity This program will uncover new, fundamental regulatory mechanisms for antifungal resistance that can later be investigated in various other microbial organisms. Our study will contribute to establish new approaches to prevent evolution of pathogen resistance to antifungals.