翻译调节促进人类真菌病原体念珠菌的应激适应。

IF 5.1 3区 生物学 Q2 GENETICS & HEREDITY
Genetics Pub Date : 2025-09-03 DOI:10.1093/genetics/iyaf134
Aishwarya Rana, Anil Thakur
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引用次数: 0

摘要

侵袭性念珠菌病提出了一个重大的医疗挑战。人类机会性真菌病原体光念珠菌(Candida glabrata)是粘膜和深层感染的原因之一,它能抵抗关键的抗真菌药物,并在宿主巨噬细胞内迅速增殖,在那里它能承受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化。本研究探讨了光棘藓对胁迫的适应与致病的分子机制。我们的研究结果表明,与酿酒葡萄球菌、白色念珠菌和耳念珠菌相比,光秃秃葡萄球菌在氧化应激和氨基酸饥饿中存活得更有效。我们观察到氨基酸饥饿和氧化应激通过gcn2介导的eIF2α磷酸化下调全局蛋白翻译,从而实现适应性恢复并激活转录因子Gcn4。gcn2Δ和gcn4Δ突变体在胁迫条件下生长受损,突出了Gcn2-Gcn4在调节胁迫特异性转录物和促进真菌存活方面的关键作用。氨基酸饥饿条件下的转录组测序表明,Gcn4协调了一系列基因的表达,主要是那些参与应激反应的基因,这些基因对营养剥夺时的生存至关重要。值得注意的是,在氧化应激下,Gcn4采用独特的适应策略,通过协调针对氧化应激的更专门的转录反应,上调一组核心氧化应激应答基因。此外,gcn2Δ和gcn4Δ在宿主巨噬细胞内表现出活性氧(ROS)水平升高和复制缺陷,Gcn4在宿主生存和毒力中至关重要。本研究强调了翻译调控在光棘草逆境适应中的重要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Translation regulation promotes stress adaptation in the human fungal pathogen Candida glabrata.

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.

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来源期刊
Genetics
Genetics GENETICS & HEREDITY-
CiteScore
6.90
自引率
6.10%
发文量
177
审稿时长
1.5 months
期刊介绍: GENETICS is published by the Genetics Society of America, a scholarly society that seeks to deepen our understanding of the living world by advancing our understanding of genetics. Since 1916, GENETICS has published high-quality, original research presenting novel findings bearing on genetics and genomics. The journal publishes empirical studies of organisms ranging from microbes to humans, as well as theoretical work. While it has an illustrious history, GENETICS has changed along with the communities it serves: it is not your mentor''s journal. The editors make decisions quickly – in around 30 days – without sacrificing the excellence and scholarship for which the journal has long been known. GENETICS is a peer reviewed, peer-edited journal, with an international reach and increasing visibility and impact. All editorial decisions are made through collaboration of at least two editors who are practicing scientists. GENETICS is constantly innovating: expanded types of content include Reviews, Commentary (current issues of interest to geneticists), Perspectives (historical), Primers (to introduce primary literature into the classroom), Toolbox Reviews, plus YeastBook, FlyBook, and WormBook (coming spring 2016). For particularly time-sensitive results, we publish Communications. As part of our mission to serve our communities, we''ve published thematic collections, including Genomic Selection, Multiparental Populations, Mouse Collaborative Cross, and the Genetics of Sex.
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