Rana Aishwarya, Thakur Anil
Regional Centre for Biotechnology, 3rd Milestone Gurgaon-Faridabad Expressway, Faridabad 121001, India.
Genetics. 2025 Sep 3;231(1). doi: 10.1093/genetics/iyaf134.
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.
侵袭性念珠菌病对医疗保健构成了重大挑战。人类机会性真菌病原体光滑念珠菌是黏膜和深部感染的病因，它对关键抗真菌药物具有抗性，并能在宿主巨噬细胞内迅速增殖，在其中它能抵御高氧化应激和氨基酸饥饿。与白色念珠菌不同，光滑念珠菌缺乏真正的菌丝，其毒力更多地依赖于应激适应机制而非丝状化。本研究探讨了光滑念珠菌中有助于其致病性的应激适应的分子机制。我们的研究结果表明，光滑念珠菌比酿酒酵母、白色念珠菌和耳念珠菌更有效地在氧化应激和氨基酸饥饿中存活。我们观察到，氨基酸饥饿和氧化应激通过Gcn2介导的真核起始因子2α磷酸化下调全局蛋白质翻译，从而实现适应性恢复并激活转录因子Gcn4。gcn2Δ和gcn4Δ突变体在应激条件下生长受损，突出了Gcn2 - Gcn4在调节应激特异性转录本和促进真菌存活中的关键作用。氨基酸饥饿条件下的转录组测序表明，Gcn4协调了一系列广泛基因的表达，主要是那些参与应激反应的基因，这些基因对于营养剥夺期间的存活至关重要。值得注意的是，在氧化应激下，Gcn4通过协调针对氧化应激的更专门的转录反应上调一组核心的氧化应激反应基因，从而采取独特的适应策略。此外，gcn2Δ和gcn4Δ在宿主巨噬细胞内表现出活性氧水平升高和复制缺陷，Gcn4在宿主存活和毒力中至关重要。本研究强调了翻译调控在光滑念珠菌应激适应中的重要性。
