Pleiotropic mutations in <i>Saccharomyces cerevisiae</i> affecting sterol uptake and metabolism

Lewis, Terry L.; Keesler, George A.; Fenner, Gregeory P.; Parks, Leo W.

doi:10.1002/yea.320040203

Cited by 80 publications

(72 citation statements)

References 22 publications

(14 reference statements)

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“…Upc2p then recruits the chromatin remodeling complex Swi/Snf to reorganize chromatin, thereby facilitating the binding of the transcriptional machinery that results in the activation of gene expression (47). Upc2p, together with the transcription factor Ecm22p, is also responsible for basal and induced expression of genes encoding enzymes of ergosterol biosynthesis in yeast (ERG1, ERG2, ERG3, ERG7, ERG25, ERG26, and ERG27), and it has been implicated in the uptake of sterols under hypoxic conditions (48)(49)(50)(51)(52).…”

Section: Fungi With the Srebp Analogue Upc2pmentioning

confidence: 99%

Regulation of hypoxia adaptation: an overlooked virulence attribute of pathogenic fungi?

Grahl¹,

Cramer²

2009

Med. Mycology

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SummaryOver the past two decades, the incidence of fungal infections has dramatically increased. This is primarily due to increases in the population of immunocompromised individuals attributed to HIV/ AIDS pandemic and immunosuppression therapies associated with organ transplantation, cancer, and other diseases where new immunomodulatory therapies are utilized. Significant advances have been made in understanding how fungi cause disease, but clearly much remains to be learned about the pathophysiology of these often lethal infections.Fungal pathogens face numerous environmental challenges as they colonize and infect mammalian hosts. Regardless of a pathogen's complexity, its ability to adapt to environmental changes is critical for its survival and ability to cause disease. For example, at sites of fungal infections, the significant influx of immune effector cells and the necrosis of tissue by the invading pathogen generate hypoxic microenvironments to which both the pathogen and host cells must adapt in order to survive. However, our current knowledge of how pathogenic fungi adapt to and survive in hypoxic conditions during fungal pathogenesis is limited. Recent studies have begun to observe that the ability to adapt to various levels of hypoxia is an important component of the virulence arsenal of pathogenic fungi. In this review, we focus on known oxygen sensing mechanisms that non-pathogenic and pathogenic fungi utilize to adapt to hypoxic microenvironments and their possible relation to fungal virulence.

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Section: Fungi With the Srebp Analogue Upc2pmentioning

confidence: 99%

Regulation of hypoxia adaptation: an overlooked virulence attribute of pathogenic fungi?

Grahl¹,

Cramer²

2009

Med. Mycology

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“…Mutations in the C-terminal domain (CTD) of Upc2 (A643V, A643T or G648D in C. albicans Upc2) result in the constitutive activation of the transcription factor (TF), resulting in the upregulation of ergosterol synthesis pathway and sterol uptake, which leads to a decreased susceptibility of the strains to azole drugs 9,10 . The gain-offunction mutation, G888D, in S. cerevisiae Upc2 results in the constitutive activation of the TF with a high level of aerobic sterol uptake 11,12 . These constitutive activation mutations are in close proximity in the C-terminal portion of Upc2, which may indicate that the CTD is important for the regulation of its transcriptional activity 9 .…”

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confidence: 99%

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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“…These genes are responsible for changes in the cell wall of yeast grown hypoxically. Upc2p has also been implicated in the uptake of sterols under hypoxic conditions (Lewis et al 1988;Crowley et al 1998;Wilcox et al 2002;Alimardani et al 2004). Normally, yeast cells take up sterols from their environment only under hypoxic conditions (Andreasen and Stier 1953), but an overactive allele of UPC2, UPC2-1, allows aerobic uptake of sterols (Lewis et al 1988).…”

mentioning

confidence: 99%

“…Upc2p has also been implicated in the uptake of sterols under hypoxic conditions (Lewis et al 1988;Crowley et al 1998;Wilcox et al 2002;Alimardani et al 2004). Normally, yeast cells take up sterols from their environment only under hypoxic conditions (Andreasen and Stier 1953), but an overactive allele of UPC2, UPC2-1, allows aerobic uptake of sterols (Lewis et al 1988). Moreover, nearly one-third of hypoxically induced genes contain at least one potential Upc2p/Ecm22p binding site (Kwast et al 2002).…”

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confidence: 99%

A Role for Sterol Levels in Oxygen Sensing in Saccharomyces cerevisiae

Davies¹,

2006

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Upc2p and Ecm22p are a pair of transcription factors responsible for the basal and induced expression of genes encoding enzymes of ergosterol biosynthesis in yeast (ERG genes). Upc2p plays a second role as a regulator of hypoxically expressed genes. Both sterols and heme depend upon molecular oxygen for their synthesis, and thus the levels of both have the potential to act as indicators of the oxygen environment of cells. Hap1p is a heme-dependent transcription factor that both Upc2 and Ecm22p depend upon for basal level expression of ERG genes. However, induction of both ERG genes and the hypoxically expressed DAN/ TIR genes by Upc2p and Ecm22p occurred in response to sterol depletion rather than to heme depletion. Indeed, upon sterol depletion, Upc2p no longer required Hap1p to activate ERG genes. Mot3p, a broadly acting repressor/activator protein, was previously shown to repress ERG gene expression, but the mechanism was unclear. We established that Mot3p bound directly to Ecm22p and repressed Ecm22p-but not Upc2p-mediated gene induction.

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Pleiotropic mutations in Saccharomyces cerevisiae affecting sterol uptake and metabolism

Cited by 80 publications

References 22 publications

Regulation of hypoxia adaptation: an overlooked virulence attribute of pathogenic fungi?

Regulation of hypoxia adaptation: an overlooked virulence attribute of pathogenic fungi?

Structural mechanism of ergosterol regulation by fungal sterol transcription factor Upc2

A Role for Sterol Levels in Oxygen Sensing in Saccharomyces cerevisiae

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