{"title":"翻译调节促进人类真菌病原体念珠菌的应激适应。","authors":"Aishwarya Rana, Anil Thakur","doi":"10.1093/genetics/iyaf134","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1000,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Translation regulation promotes stress adaptation in the human fungal pathogen Candida glabrata.\",\"authors\":\"Aishwarya Rana, Anil Thakur\",\"doi\":\"10.1093/genetics/iyaf134\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":48925,\"journal\":{\"name\":\"Genetics\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":5.1000,\"publicationDate\":\"2025-09-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Genetics\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1093/genetics/iyaf134\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genetics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1093/genetics/iyaf134","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
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.
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.