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Translation Regulation Promotes Stress Adaptation in Candida glabrata

ABSTRACT: 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.

ORGANISM(S): Nakaseomyces glabratus

PROVIDER: GSE283533 | GEO | 2025/07/14

REPOSITORIES: GEO

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Project description:Two nutrient sensing and regulatory pathways, the general amino acid control (GAAC) and the target of rapamycin (TOR), control yeast growth and metabolism in response to changes in nutrient availability. Starvation for amino acids activates the GAAC pathway, involving Gcn2p phosphorylation of eIF2 and preferential translation of GCN4, a transcription activator of genes involved in amino acid metabolism. TOR senses nitrogen availability and regulates gene expression through transcription factors, such as Gln3p. We used microarray analyses to address the integration of the GAAC and TOR pathways in directing the yeast transcriptome in response to amino acid starvation and rapamycin treatment. Of the ~2500 genes whose expression was changed by 2-fold or greater, Gcn4p and Gln3p were required for 542 and 657 genes, respectively. While Gcn4p activates a common core of 57 genes in response to amino acid starvation or rapamycin treatment, the different stress arrangements allow for variations in Gcn4p-directed transcription. With few exceptions, genes requiring Gcn2p eIF2 kinase for induced expression also required Gcn4p, emphasizing the role of Gcn2p as an upstream activator of Gcn4p-directed transcription. There is also significant coordination between the GAAC and TOR pathways, with Gcn4p being required for activation of more genes during rapamycin treatment than Gln3p. Importantly, TOR regulates the GAAC-directed transcription of genes required for assimilation of nitrogen sources, such as Î³-amino-butyric acid. Therefore, yeast has integrated gene expression responses to amino acid abundance and nitrogen source quality through the control of Gcn2p phosphorylation of eIF2 and GCN4 translation. Keywords: gene expression In this study, we carried out microarray analyses in a collection of yeast strains deleted for GCN2, GCN4, and GLN3, individually or in combinations, to explore the importance of the TOR and GAAC pathways in directing the transcriptome in response to amino acid starvation and rapamycin treatment.

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Translation Regulation Promotes Stress Adaptation in Candida glabrata

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