Erg6 Acts as a Downstream Effector of the Transcription Factor Flo8 To Regulate Biofilm Formation in Candida albicans

Jin, Xueyang; Luan, Xiaoyi; Xie, Fei; Chang, Wenqiang; Lou, Hongxiang

doi:10.1128/spectrum.00393-23

Cited by 9 publications

(21 citation statements)

References 18 publications

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“…However, erg6 loss-of-function mutations in these organisms cause alteration of drug susceptibility and defective growth phenotypes related to membrane integrity and permeability. Recent exciting studies have shown that loss of C. albicans Erg6 activity, either through genetic downregulation of ERG6 gene transcription or through pharmacologic inhibition of Erg6 protein activity with a novel small molecule, blocks the pathogenic yeast-to-hyphae transition and significantly reduces virulence 19 , 20 . Studies of Erg6 in filamentous fungi are relatively very limited.…”

Section: Introductionmentioning

confidence: 99%

The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species

Xie,

Rybak,

Martin-Vicente

et al. 2024

Nat Commun

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Triazoles, the most widely used class of antifungal drugs, inhibit the biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Inhibition of a separate ergosterol biosynthetic step, catalyzed by the sterol C-24 methyltransferase Erg6, reduces the virulence of pathogenic yeasts, but its effects on filamentous fungal pathogens like Aspergillus fumigatus remain unexplored. Here, we show that the lipid droplet-associated enzyme Erg6 is essential for the viability of A. fumigatus and other Aspergillus species, including A. lentulus, A. terreus, and A. nidulans. Downregulation of erg6 causes loss of sterol-rich membrane domains required for apical extension of hyphae, as well as altered sterol profiles consistent with the Erg6 enzyme functioning upstream of the triazole drug target, Cyp51A/Cyp51B. Unexpectedly, erg6-repressed strains display wild-type susceptibility against the ergosterol-active triazole and polyene antifungals. Finally, we show that erg6 repression results in significant reduction in mortality in a murine model of invasive aspergillosis. Taken together with recent studies, our work supports Erg6 as a potentially pan-fungal drug target.

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Section: Introductionmentioning

confidence: 99%

The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species

Xie,

Rybak,

Martin-Vicente

et al. 2024

Nat Commun

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“…The pGADT7 and pHIS2 plasmids were employed for yeast one-hybrid assay [ 25 ]. The HOF1 promoter, in different lengths, was amplified by PCR and inserted into the EcoR I site of the pHIS2 plasmid as bait using the Universal One Step Cloning Kit (Yeasen, Shanghai, China).…”

Section: Methodsmentioning

confidence: 99%

DNA Damage Checkpoints Govern Global Gene Transcription and Exhibit Species-Specific Regulation on HOF1 in Candida albicans

Zhang,

Cai,

Chen

et al. 2024

JoF

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DNA damage checkpoints are essential for coordinating cell cycle arrest and gene transcription during DNA damage response. Exploring the targets of checkpoint kinases in Saccharomyces cerevisiae and other fungi has expanded our comprehension of the downstream pathways involved in DNA damage response. While the function of checkpoint kinases, specifically Rad53, is well documented in the fungal pathogen Candida albicans, their targets remain poorly understood. In this study, we explored the impact of deleting RAD53 on the global transcription profiles and observed alterations in genes associated with ribosome biogenesis, DNA replication, and cell cycle. However, the deletion of RAD53 only affected a limited number of known DNA damage-responsive genes, including MRV6 and HMX1. Unlike S. cerevisiae, the downregulation of HOF1 transcription in C. albicans under the influence of Methyl Methanesulfonate (MMS) did not depend on Dun1 but still relied on Rad53 and Rad9. In addition, the transcription factor Mcm1 was identified as a regulator of HOF1 transcription, with evidence of dynamic binding to its promoter region; however, this dynamic binding was interrupted following the deletion of RAD53. Furthermore, Rad53 was observed to directly interact with the promoter region of HOF1, thus suggesting a potential role in governing its transcription. Overall, checkpoints regulate global gene transcription in C. albicans and show species-specific regulation on HOF1; these discoveries improve our understanding of the signaling pathway related to checkpoints in this pathogen.

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“…G. mellonella has been used to study many fungi, including Aspergillus spp., Candida spp., Cryptococcus spp., Conidiobolus coronatus , Histoplasma capsulatum , Madurella mycetomatis , Malassezia spp. and Paraccocidioides brasiliensis [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 ].…”

Section: G Mellonella As a Model To Study Fungi In Vivomentioning

confidence: 99%

“…Categorising studies using G. mellonella larvae to assess virulence or drug efficacy is a challenging task. It is more appropriate to evaluate the work based on different fungal genera since some species have undergone extensive research in recent years [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 ].…”

Section: G Mellonella As a Model To Study Fungi In Vivomentioning

confidence: 99%

“…Some authors have highlighted the induction of the inflammatory response in G. mellonella in C. albicans strains with deletion of the α-subunit of F1Fo-ATP synthase compared to the wild-type strain [ 73 ]. It has been shown that Erg 6 overexpression acts as an effector of the Flo8 transcription factor and regulates biofilm and virulence in G. mellonella [ 74 ].…”

Section: G Mellonella As a Model To Study Fungi In Vivomentioning

confidence: 99%

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Galleria mellonella as a Model for the Study of Fungal Pathogens: Advantages and Disadvantages

Giammarino,

Bellucci,

Angiolella

2024

Pathogens

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The study of pathogenicity and virulence of fungal strains, in vivo in the preclinical phase, is carried out through the use of animal models belonging to various classes of mammals (rodents, leproids, etc.). Although animals are functionally more similar to humans, these studies have some limitations in terms of ethics (animal suffering), user-friendliness, cost-effectiveness, timing (physiological response time) and logistics (need for adequately equipped laboratories). A good in vivo model must possess some optimal characteristics to be used, such as rapid growth, small size and short life cycle. For this reason, insects, such as Galleria mellonella (Lepidoptera), Drosophila melanogaster (Diptera) and Bombyx mori (Lepidoptera), have been widely used as alternative non-mammalian models. Due to their simplicity of use and low cost, the larvae of G. mellonella represent an optimal model above all to evaluate the virulence of fungal pathogens and the use of antifungal treatments (either single or in combination with biologically active compounds). A further advantage is also represented by their simple neuronal system limiting the suffering of the animal itself, their ability to survive at near-body ambient temperatures as well as the expression of proteins able to recognise combined pathogens following the three R principles (replacement, refinement and reduction). This review aims to assess the validity as well as the advantages and disadvantages of replacing mammalian classes with G. mellonella as an in vivo study model for preclinical experimentation.

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Erg6 Acts as a Downstream Effector of the Transcription Factor Flo8 To Regulate Biofilm Formation in Candida albicans

Abstract: Biofilm formation by C. albicans hinders its eradication by immune cells and antifungal drugs. Flo8 is an important morphogenetic transcription factor that regulates the biofilm formation and in vivo virulence of C. albicans .

Cited by 9 publications

References 18 publications

The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species

The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species

DNA Damage Checkpoints Govern Global Gene Transcription and Exhibit Species-Specific Regulation on HOF1 in Candida albicans

Galleria mellonella as a Model for the Study of Fungal Pathogens: Advantages and Disadvantages

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