Translation regulation promotes stress adaptation in the human fungal pathogen Candida glabrata

Abstract Invasive candidiasis presents a significant healthcare challenge. The human opportunistic fungal pathogen Candida glabrata, a cause of mucosal and deep-seated infections, resists key antifungal drugs and rapidly proliferates within host macrophages, where it withstands high oxidative stress and amino acid starvation. Unlike C. albicans, C. glabrata lacks true hyphae and relies more on stress adaptation mechanisms than filamentation for virulence. 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 Saccharomyces cerevisiae, C. albicans, and C. auris. We observed that amino acid starvation and oxidative stress downregulate global protein translation through Gcn2-mediated eukaryotic initiation factor 2α phosphorylation, enabling adaptive recovery and activating the transcription factor Gcn4. The gcn2Δ and gcn4Δ mutants had impaired growth under stress conditions, highlighting the pivotal role of Gcn2–Gcn4 in regulating stress-specific transcripts and promoting fungal survival. Transcriptome sequencing under amino acid starvation conditions demonstrated that Gcn4 orchestrates the expression of a broad array of genes, primarily those involved in stress responses, which are essential for survival during nutrient deprivation. Notably, under oxidative stress, Gcn4 adopts unique adaptation strategies by upregulating a core set of oxidative stress-responsive genes by coordinating a more specialized transcriptional response tailored to oxidative stress. Additionally, gcn2Δ and gcn4Δ exhibited elevated levels of reactive oxygen species and defective replication within host macrophages, with Gcn4 being crucial in host survival and virulence. This study underscores the importance of translational regulation in stress adaptation of C. glabrata.