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A single gene mutation underpins metabolic adaptation and acquisition of filamentous competence in the emerging fungal pathogen Candida auris

ABSTRACT:

Filamentous cell growth is a vital property of fungal pathogens. The mechanisms of filamentation in the emerging multidrug-resistant fungal pathogen Candida auris are poorly understood. Here, we show that exposure of C. auris to glycerol triggers a rod-like filamentation-competent (RL-FC) phenotype, which forms elongated filamentous cells after a prolonged culture period. Whole-genome sequencing analysis reveals that all RL-FC isolates harbor a mutation in the C2H2 zinc finger transcription factor-encoding gene GFC1 (Gfc1 variants). Deletion of GFC1 leads to an RL-FC phenotype similar to that observed in Gfc1 variants. We further demonstrate that GFC1 mutation causes enhanced fatty acid β-oxidation metabolism and thereby promotes RL-FC/filamentous growth. This regulation is achieved through a Multiple Carbon source Utilizer (Mcu1)-dependent mechanism. Interestingly, both the evolved RL-FC isolates and the gfc1Δ mutant exhibit an enhanced ability to colonize the skin. Our results reveal that glycerol-mediated GFC1 mutations are beneficial during C. auris skin colonization and infection.

INSTRUMENT(S): Gas Chromatography MS - positive

PROVIDER: MTBLS9053 | MetaboLights | 2024-07-04

REPOSITORIES: MetaboLights

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			Action	DRS
	T23164326a.mzML	Mzml
	T23164327a.mzML	Mzml
	T23164328a.mzML	Mzml
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	T23164330a.mzML	Mzml

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Similar Datasets

A single gene mutation underpins metabolic adaptation and acquisition of filamentous competence in the emerging fungal pathogen Candida auris

Project description:Filamentous cell growth is a vital property of fungal pathogens. The mechanisms of filamentation in the emerging multidrug-resistant fungal pathogen Candida auris are poorly understood. Here, we show that exposure of C. auris to glycerol triggers a rod-like filamentation-competent (RL-FC) phenotype, which forms elongated filamentous cells after a prolonged culture period. Whole-genome sequencing analysis reveals that all RL-FC isolates harbor a mutation in the C2H2 zinc finger transcription factor-encoding gene GFC1 (Gfc1 variants). Deletion of GFC1 leads to an RL-FC phenotype similar to that observed in Gfc1 variants. We further demonstrate that GFC1 mutation causes enhanced fatty acid β-oxidation metabolism and thereby promotes RL-FC/filamentous growth. This regulation is achieved through a Multiple Carbon source Utilizer (Mcu1)-dependent mechanism. Interestingly, both the evolved RL-FC isolates and the gfc1Δ mutant exhibit an enhanced ability to colonize the skin. Our results reveal that glycerol-mediated GFC1 mutations are beneficial during C. auris skin colonization and infection.

2024-06-12 | PXD047167 | Pride

A conserved C2H2 zinc finger protein, Rel1, links ribosome biogenesis to sexual development and environmental stress response in a ubiquitous human fungal pathogen

Project description:Sexual development is a fundamental process that promotes infection and the emergence of highly virulent and drug-resistant isolates in the human fungal pathogen Cryptococcus neoformans. While the genetic factors involved in sexual life cycle have been extensively investigated in this pathogenic fungus, the critical regulator(s) beyond transcriptional machinery remains poorly understood. Rei1, a conserved C2H2-type zinc finger protein, functions as a 60S ribosome biogenesis factor and plays a crucial role in maintaining cellular growth at low temperature in yeast. In this study, we identified a yeast Rei1-like protein, Rel1, based on its encoding gene that was dynamically up-regulated during unisexual reproduction in C. neoformans. Similar to Rei1’s role in yeast, disruption of REL1 gene results in significant growth retardation under low temperature conditions. Consistent with its upregulation during sexual development, REL1 deletion compromised the entire sexual cycle, including yeast-hyphae morphogenesis, basidial differentiation, meiosis and sporulation. RNA-Seq analysis revealed that Rei1 is required for the transcriptional activation of key sexual reproduction gene sets involved in mating response, morphogenesis and meiosis, suggesting a potential link between ribosome biogenesis and sexual development in C. neoformans. Furthermore, REL1 disruption increased susceptibility to the antifungal drug 5’-flucytosine (5’-FC) but enhanced resistance to fluconazole, indicating its differential role in antifungal drugs resistance mechanisms. Collectively, this study provides critical insights into how C. neoformans utilize a conserved ribosome biogenesis factor to coordinate cold resistance, sexual development, and antifungal susceptibility, highlighting both conserved and divergent functions of this C2H2 zinc-finger protein compared to its ortholog in budding yeast.

2025-11-11 | GSE296246 | GEO

RNA-Seq of mouse embryonic stem cells in response to changes in Sall4

Project description:Sall4 is a stem cell factor which is important for embryogenesis. We have genetically modified Sall4 in mouse embryonic stem cells to access the transcriptional changes. There are three different genetic modifications for the ES cells in the form of Sall4 Knockout (KO), Sall4 Zinc Finger Cluster 4 Mutation (ZFC4mut) and Sall4 Zinc Finger Cluster 4 Deletion (ZFC4Δ) respectively that we have considered for our study.

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Novel genetic mutations in pyrimidine salvage pathway enzymes from Cryptococcus neoformans contribute to reduced susceptibility against 5-fluorocytosine

Project description:The most common cause of cryptococcal meningitis is Cryptococcus neoformans. The addition of 5-fluorocytosine to the treatment of patient with this potentially fatal infection significantly improves disease outcome. However, developing resistance to this drug is a serious problem in patient management. In this study, we investigated the molecular mechanisms causing 5-FC resistance in three clinical isolates of C. neoformans using genomic and proteomic approaches. Our findings show that genetic alterations in genes involved in the pyrimidine salvage pathway caused 5-FC resistance in these isolates. Specifically, one isolate had a missense mutation (E64G) in the uracil phosphoribosyl transferase gene (FUR1), another isolate had a large deletion spanning the cytosine deaminase gene (FCY1), and the third isolate had a point mutation in the same gene leading to a truncated protein at amino acid 164 (STOPW164*). Proteomic data confirmed that the genetic changes led to the absence or decreased the amount of the enzymes in the 5-FC resistant isolates. Transformation experiments confirmed that the genetic changes ultimately affected 5-FC susceptibility, providing further evidence of the effect of the genetic changes on 5-FC susceptibility.

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RNA-Seq of Sall4 mutants in mouse embryonic stem cells

Project description:Sall4 is a stem cell factor which is important for embryogenesis. We have genetically modified Sall4 in mouse embryonic stem cells to access the transcriptional changes. There are three different genetic modifications for the ES cells in the form of Sall4 Knockout (KO), Sall4 Zinc Finger Cluster 4 Mutation (ZFC4mut) and Sall4 Zinc Finger Cluster 1-2 Deletion (ZFC1-2Δ) respectively that we have considered for our study.

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Project description:Sall4 is a stem cell factor which is important for embryogenesis. We have genetically modified Sall4 in mouse embryonic stem cells to access the preference of Sall4 binding site. There are three different genetic modifications for the ES cells in the form of Sall4 Knockout (KO), Sall4 Zinc Finger Cluster 4 Mutation (ZFC4mut) and Sall4 Zinc Finger Cluster 1-2 Deletion (ZFC1-2Δ) respectively that we have considered for our study.

2021-01-05 | E-MTAB-9197 | biostudies-arrayexpress

Adaptation of commensal proliferating Escherichia coli to the intestinal tract of young children with cystic fibrosis

Project description:E. coli isolates from different CF patients demonstrate increased growth rate when grown with glycerol, a major component of fecal fat, as the sole carbon source compared to E. coli from healthy controls. CF and control E. coli isolates have differential gene expression when grown in minimal media with glycerol as the sole carbon source. While CF isolates display a growth promoting transcriptional profile, control isolates engage stress and stationary phase programs, which likely results in slower growth rates.

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Timecourse RNA-seq of mouse embryonic stem cells during neural differentiation

Project description:Sall4 is a stem cell factor which is important for embryogenesis. We have genetically modified Sall4 in mouse embryonic stem cells to access the transcriptional changes. There are three different genetic modifications for the ES cells in the form of Sall4 Knockout (KO), Sall4 Zinc Finger Cluster 4 Mutation (ZFC4mut) and Sall4 Zinc Finger Cluster 1-2 Deletion (ZFC1-2Δ) respectively that we have considered for our study. Cells were subjected to neural differentiation and directly lysed on the plate at the appropriate timepoint and RNA was sequenced.

2021-01-05 | E-MTAB-9198 | biostudies-arrayexpress

Adaptation of Cupriavidus metallidurans CH34 to toxic zinc concentrations involves an uncharacterized ABC-type transporter

Project description:Cupriavidus metallidurans CH34 is a well-studied metal-resistant β-proteobacterium and contains a battery of genes involved in the resistance and processing of numerous metals. Here, we performed a directed evolution experiment to obtain derivatives adapted to grow in the presence of zinc at concentrations above the minimal inhibitory concentration for the parental strain. Genetic characterization of one derivative, CH34ZnR, which was also more resistant to cadmium, revealed seven mutations, including inactivation of glpR coding for a DeoR-type transcriptional repressor by insertion of IS1088. The latter resulted in the constitutive expression of the neighboring ABC-type transporter. GlpR and the adjacent ABC transporter are highly similar to the glycerol operon regulator and ATP-driven glycerol importer of Rhizobium leguminosarum bv. viciae VF39, respectively. Deletion of glpR or the ABC transporter and complementation of CH34ZnR with the parental glpR gene further demonstrated that loss of GlpR function, with concomitant induction of the adjacent ABC transporter, is pivotal in the observed phenotype. Moreover, addition of glycerol, presumably by glycerol-mediated reduced GlpR activity, also promoted increased zinc and cadmium resistance. Thus, the ABC-type transporter is proposed to be a new adaptation route during exposure to toxic zinc concentrations.

2021-03-03 | GSE156826 | GEO

A second genetic screen for gurken mRNA mislocalisation reveals novel phenotypes of the piRNA pathway mutants in Drosophila [ncRNA-seq]

Project description:Transposon silencing is essential for germ line development. In Drosophila oogenesis, DNA damage caused by transposon activation affects microtubule-dependent mRNA localisation in the oocyte and impairs embryonic axes formation. Our previous EMS mutagenesis screen for gurken mRNA mislocalisaiton on Chromosome 3L of Drosophila melanogaster identified several piRNA pathway mutants (PMID: 24531791). Here we report the screen for Chromosome 3R. We identified 10 mutation groups disrupting gurken mRNA localisation and other mutations affecting different aspects of oogenesis. We found that mutations in karyopherin-b3 affect localisation and translation of gurken mRNA in a transposon silencing-independent manner. Characterisation of the new mutation in vreteno revealed that the piRNA pathway is essential for the basal stalk development, the process of holding the ovariole and encapsulating the first egg chambers. Females transheterozygous for vreteno and armitage mutations both showed abnormal basal stalks, defective egg chamber formation and loss of germ line cells. We also found that the mutation in the Zinc Finger motif of Spindle-E shows a hypomorphic transposon activation phenotype, consistent with the previous study (PMID: 25239103). Further characterisation showed that the Zinc Finger is required for robust ping-pong piRNA biogenesis and the nuage localisaiton of AGO3, but not of Aubergine, suggesting that it is involved in a specific step of ping-pong biogenesis.

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