Zinc Finger Transcription Factors Displaced SREBP Proteins as the Major Sterol Regulators during Saccharomycotina Evolution

Maguire, Sarah; Wang, Can; Holland, Linda; Brunel, François; Neuvéglise, Cécile; Nicaud, Jean‐Marc; Zavřel, Martin; White, Theodore C.; Wolfe, Kenneth H.; Butler, Geraldine

doi:10.1371/journal.pgen.1004076

Cited by 54 publications

(79 citation statements)

References 97 publications

(157 reference statements)

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“…The lack of sequence and structural similarities of fungal zinc cluster TFs and metazoan NRs suggests that the architectural and functional similarities are the product of convergent evolution with common mechanistic strategy. Phylogenetic analysis shows that the orthologues of Upc2 are only identifiable within the Saccharomycotina and Upc2/Ecm22 proteins form monophyletic clade that is not closely related to any other Zn 2 -Cys 6 proteins of Saccharomycotina 5 . The budding yeast, S. cerevisiae, contains around 50 Zn 2 -Cys 6 TFs 39 .…”

Section: Resultsmentioning

confidence: 94%

“…Therefore, fungal zinc cluster TFs seem to have evolved to monitor and regulate the metabolic pathways by sensing their key compounds. Some fungal species that contains SREBP homologues do not harbour the UPC2 gene and vice versa, implying that they might have developed separate regulatory mechanism of sterol homeostasis during evolution 5 . Depletion of sterol levels by azole antifungals stimulates the activation of sterol uptake genes by Upc2 (ref.…”

Section: Discussionmentioning

confidence: 99%

“…In some fungal species, such as Schizosaccharomyces pombe, it is mediated by hypoxic regulatory proteins, Sre1 and Scp1, which share common features with the mammalian sterol regulatory element-binding proteins (SREBPs) and SREBP cleavage-activating protein 3,4 . However, many other fungal species, including Saccharomyces cerevisiae and Candida species, lack protein homologues of the mammalian cholesterol regulators and appear to have evolved distinct regulatory mechanism 5 . In S. cerevisiae, Upc2 and Ecm22, two similar zinc finger transcriptional factors, have been implicated in ergosterol regulation by binding to the promoters of ergosterol biosynthetic and sterol uptake genes and activating the transcription on sterol depletion 2,6 .…”

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confidence: 99%

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Structural mechanism of ergosterol regulation by fungal sterol transcription factor Upc2

et al. 2015

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Transcriptional regulation of ergosterol biosynthesis in fungi is crucial for sterol homeostasis and for resistance to azole drugs. In Saccharomyces cerevisiae, the Upc2 transcription factor activates the expression of related genes in response to sterol depletion by poorly understood mechanisms. We have determined the structure of the C-terminal domain (CTD) of Upc2, which displays a novel a-helical fold with a deep hydrophobic pocket. We discovered that the conserved CTD is a ligand-binding domain and senses the ergosterol level in the cell. Ergosterol binding represses its transcription activity, while dissociation of the ligand leads to relocalization of Upc2 from cytosol to nucleus for transcriptional activation. The C-terminal activation loop is essential for ligand binding and for transcriptional regulation. Our findings highlight that Upc2 represents a novel class of fungal zinc cluster transcription factors, which can serve as a target for the developments of antifungal therapeutics.

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Section: Resultsmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Structural mechanism of ergosterol regulation by fungal sterol transcription factor Upc2

et al. 2015

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“…Among the haploid species, C. lusitaniae, although relatively rare clinically, is nonetheless much more common than M. guilliermondii, which in turn is more common than D. hansenii (25). Thus, we sought to add to the existing bioinformatics comparisons based on genome sequence and predicted protein content (17,26,27) by understanding the phenotypic differences that may contribute to virulence in these species.…”

Section: Resultsmentioning

confidence: 99%

Characterization of Virulence-Related Phenotypes in Candida Species of the CUG Clade

Priest

Lorenz

2015

Eukaryot Cell

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bCandida species cause a variety of mucosal and invasive infections and are, collectively, the most important human fungal pathogens in the developed world. The majority of these infections result from a few related species within the "CUG clade," so named because they use a nonstandard translation for that codon. Some members of the CUG clade, such as Candida albicans, present significant clinical problems, whereas others, such as Candida (Meyerozyma) guilliermondii, are uncommon in patients. The differences in incidence rates are imperfectly correlated with virulence in animal models of infection, but comparative analyses that might provide an explanation for why some species are effective pathogens and others are not have been rare or incomplete. To better understand the phenotypic basis for these differences, we characterized eight CUG clade species-C. albicans, C. dubliniensis, C. tropicalis, C. parapsilosis, Clavispora lusitaniae, M. guilliermondii, Debaryomyces hansenii, and Lodderomyces elongisporus-for host-relevant phenotypes, including nutrient utilization, stress tolerance, morphogenesis, interactions with phagocytes, and biofilm formation. Two species deviated from expectations based on animal studies and human incidence. C. dubliniensis was quite robust, grouping in nearly all assays with the most virulent species, C. albicans and C. tropicalis, whereas C. parapsilosis was substantially less fit than might be expected from its clinical importance. These findings confirm the utility of in vitro measures of virulence and provide insight into the evolution of virulence in the CUG clade. Candida species are the most important fungal pathogens of humans and are collectively responsible for a vast number of infections. These range from superficial mucosal infections such as vulvovaginal candidiasis, and oropharyngeal thrush, to lifethreatening infections such as disseminated hematogenous and invasive candidiasis. These latter infections have steadily increased in incidence in the last 30 years and are associated with a stubbornly high mortality rate as a result of the underlying immunodeficiency of the patients and inadequate diagnostics and treatments (1).Of the approximately 150 species in the genus, 95% of infections are caused by just four species: C. albicans, C. tropicalis, C. parapsilosis, and C. glabrata (2-4). C. albicans is the dominant species, representing about half of disseminated disease and an even greater percentage of mucosal infections. Other clinically relevant species include Clavispora lusitaniae (anamorph: Candida lusitaniae), M. guilliermondii (anamorph: Candida guilliermondii), C. krusei, and C. dubliniensis, while D. hansenii (synonym: Candida famata) and Lodderomyces elongisporus are subjects of rare clinical reports. Because the genus Candida is polyphyletic, a better sense of evolutionary relationships comes in the "CUG clade," a grouping of species that use an alternative genetic code in which that codon specifies serine rather than leucine (5, 6). The CUG clade encompasses ...

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“…However, Upc2 is not responsible for hypoxia-induced expression of glycolytic genes or decreased expression of genes in respiratory pathways (30). Interestingly, Yarrowia lipolytica, which represents the most divergent lineage of the Saccharomycotina, has both SREBP and Upc2 (31). Both SREBP and Upc2 play a role in response to hypoxic conditions in Y. lipolytica, but Upc2 is the major regulator of sterol genes.…”

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confidence: 99%

Function and Regulation of Cph2 in Candida albicans

et al. 2015

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dCandida albicans is associated with humans as both a harmless commensal organism and a pathogen. Cph2 is a transcription factor whose DNA binding domain is similar to that of mammalian sterol response element binding proteins (SREBPs). SREBPs are master regulators of cellular cholesterol levels and are highly conserved from fungi to mammals. However, ergosterol biosynthesis is regulated by the zinc finger transcription factor Upc2 in C. albicans and several other yeasts. Cph2 is not necessary for ergosterol biosynthesis but is important for colonization in the murine gastrointestinal (GI) tract. Here we demonstrate that Cph2 is a membrane-associated transcription factor that is processed to release the N-terminal DNA binding domain like SREBPs, but its cleavage is not regulated by cellular levels of ergosterol or oxygen. Chromatin immunoprecipitation sequencing (ChIP-seq) shows that Cph2 binds to the promoters of HMS1 and other components of the regulatory circuit for GI tract colonization. In addition, 50% of Cph2 targets are also bound by Hms1 and other factors of the regulatory circuit. Several common targets function at the head of the glycolysis pathway. Thus, Cph2 is an integral part of the regulatory circuit for GI colonization that regulates glycolytic flux. Transcriptome sequencing (RNA-seq) shows a significant overlap in genes differentially regulated by Cph2 and hypoxia, and Cph2 is important for optimal expression of some hypoxia-responsive genes in glycolysis and the citric acid cycle. We suggest that Cph2 and Upc2 regulate hypoxia-responsive expression in different pathways, consistent with a synthetic lethal defect of the cph2 upc2 double mutant in hypoxia.

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Zinc Finger Transcription Factors Displaced SREBP Proteins as the Major Sterol Regulators during Saccharomycotina Evolution

Cited by 54 publications

References 97 publications

Structural mechanism of ergosterol regulation by fungal sterol transcription factor Upc2

Structural mechanism of ergosterol regulation by fungal sterol transcription factor Upc2

Characterization of Virulence-Related Phenotypes in Candida Species of the CUG Clade

Function and Regulation of Cph2 in Candida albicans

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