Translation Regulation Promotes Stress Adaptation in Candida glabrata

Candida glabrata is an important human fungal pathogen leading cause of non-albicans Candida infections. C. glabrata exhibits resistance to key antifungal drugs, rapidly replicates and divides in host macrophages and withstands highly stressful host conditions. This study explores the molecular mechanisms underlying stress adaptations in C. glabrata that contribute to its pathogenicity. Our findings revealed that C. glabrata survives oxidative stress and amino acid starvation more effectively than S. cerevisiae, C. albicans, and C. auris. We noted that Gcn2 kinase and Gcn4 play critical roles in this adaptation as Gcn2 phosphorylates eIF2α and downregulates the global protein translation, activating GCN4. RNA sequencing of WT and gcn4 mutant revealed that GCN4 activation during stress orchestrates the expression of stress-responsive genes vital for survival during amino acid starvation and oxidative stress. Ultimately assisting in the stress adaptative transcriptome. Thus, this study highlights the critical role of the Gcn2–Gcn4 pathway in stress adaptation in C. glabrata. The WT and gcn4 mutant at log phase O.D. in Simple Dextrose (SD) minimal media were treated with 5 mM 3AT (3-amino triazole) that provided histidine starvation and ultimately amino acid starvation and 10 mM H2O2 (Hydrogen peroxide) as a ROS agent generating oxidative stress. Both treatments were given for 30 minutes keeping the untreated control with three individual replicates. The cells were pelleted, and total RNA was extracted from the untreated and treated samples for both stress and biological replicates. Samples were then sent for transcriptome profiling.