Sterol uptake in Candida glabrata: Rescue of sterol auxotrophic strains

Bard, Martin; Sturm, Aaron M.; Pierson, C. A.; Brown, Shaleak; Rogers, Kristina M.; Nabinger, Sarah C.; Eckstein, James A.; Barbuch, Robert J.; Lees, N. Douglas; Howell, S. A.; Hazen, Kevin C.

doi:10.1016/j.diagmicrobio.2005.03.001

Cited by 48 publications

(51 citation statements)

References 23 publications

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“…Cholesterol uptake and metabolism within cells is more thoroughly characterized due to its better commercial availability as a fluorescently or radiolabeled substrate; thus, it is used for most of the uptake studies. Although there are several structural differences between cholesterol and ergosterol, they both efficiently support the growth of S. cerevisiae and C. glabrata incapable of ergosterol biosynthesis (15,27). The third species, C. albicans, has never been directly analyzed for sterol import.…”

Section: Resultsmentioning

confidence: 99%

“…No mechanism of sterol uptake was identified in previous work (27,31,32). Unlike S. cerevisiae and C. glabrata, there is lack of response to exogenous sterols by C. albicans wild-type, CaHEM1-null mutant, or sterol auxotrophs (27). Moreover, no clear orthologs of ScAUS1 or ScPDR11 can be identified in the C. albicans genome.…”

mentioning

confidence: 92%

“…Previous work suggests that C. albicans, unlike the two species mentioned above, depends solely on the synthesis of endogenous ergosterol. No mechanism of sterol uptake was identified in previous work (27,31,32). Unlike S. cerevisiae and C. glabrata, there is lack of response to exogenous sterols by C. albicans wild-type, CaHEM1-null mutant, or sterol auxotrophs (27).…”

mentioning

confidence: 98%

“…However, C. glabrata differs in the conditions of sterol import. Recent studies (27,28) revealed that C. glabrata wild-type strains import sterol under aerobic conditions, independent of the mutations in heme synthesis or the Upc2 orthologs that are required for S. cerevisiae aerobic sterol uptake. Wild-type C. glabrata responds to sterol-containing serum and bile, but not free cholesterol, whereas CgERG mutants can utilize free sterols, as well as components containing sterol.…”

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confidence: 99%

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Comparison of Sterol Import under Aerobic and Anaerobic Conditions in Three Fungal Species, Candida albicans, Candida glabrata, and Saccharomyces cerevisiae

2013

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bSterol import has been characterized under various conditions in three distinct fungal species, the model organism Saccharomyces cerevisiae and two human fungal pathogens Candida glabrata and Candida albicans, employing cholesterol, the sterol of higher eukaryotes, as well as its fungal equivalent, ergosterol. Import was confirmed by the detection of esterified cholesterol within the cells. Comparing the three fungal species, we observe sterol import under three different conditions. First, as previously well characterized, we observe sterol import under low oxygen levels in S. cerevisiae and C. glabrata, which is dependent on the transcription factor Upc2 and/or its orthologs or paralogs. Second, we observe sterol import under aerobic conditions exclusively in the two pathogenic fungi C. glabrata and C. albicans. Uptake emerges during post-exponential-growth phases, is independent of the characterized Upc2-pathway and is slower compared to the anaerobic uptake in S. cerevisiae and C. glabrata. Third, we observe under normoxic conditions in C. glabrata that Upc2-dependent sterol import can be induced in the presence of fetal bovine serum together with fluconazole. In summary, C. glabrata imports sterols both in aerobic and anaerobic conditions, and the limited aerobic uptake can be further stimulated by the presence of serum together with fluconazole. S. cerevisiae imports sterols only in anaerobic conditions, demonstrating aerobic sterol exclusion. Finally, C. albicans imports sterols exclusively aerobically in post-exponential-growth phases, independent of Upc2. For the first time, we provide direct evidence of sterol import into the human fungal pathogen C. albicans, which until now was believed to be incapable of active sterol import.

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Section: Resultsmentioning

confidence: 99%

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confidence: 92%

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confidence: 98%

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confidence: 99%

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Comparison of Sterol Import under Aerobic and Anaerobic Conditions in Three Fungal Species, Candida albicans, Candida glabrata, and Saccharomyces cerevisiae

2013

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“…Although there are several structural differences between cholesterol and ergosterol, they both efficiently support the growth of S. cerevisiae and C. glabrata incapable of ergosterol biosynthesis 47 . Since the human body under azole treatment provides conditions favouring the stimulation of sterol import from the fungal environment, the ability of C. glabrata to replace ergosterol with a host sterol may be responsible for its elevated azole resistance in vivo 6,47 . The deletion of UPC2 leads to anaerobic inviability and high susceptibility to azole antifungals in S. cerevisiae and in C. albicans 6,14 .…”

Section: Discussionmentioning

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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Protein‐facilitated transport of hydrophobic molecules across the yeast plasma membrane

2019

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In yeasts, the plasma membrane forms the barrier that protects the cell from the outside world, but also gathers and keeps valuable compounds inside. Although it is often suggested that hydrophobic molecules surpass this checkpoint by simple diffusion, it now becomes evident that protein‐facilitated transport mechanisms allow for selective import and export of triglycerides, fatty acids, alkanes, and sterols in yeasts. During biomass production, hydrophobic carbon sources enter and exit the cell efficiently in a strictly regulated manner that helps avoid toxicity. Furthermore, various molecules, such as yeast pheromones, secondary metabolites and xenobiotics, are exported to ensure cell–cell communication, or increase chances of survival. This review summarizes the current knowledge on how hydrophobic compounds interact with protein‐facilitated transport systems on the plasma membrane and how selective import and export across the yeast plasma membrane is achieved. Both the model organism Saccharomyces cerevisiae, as well as unconventional yeasts are discussed.

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Sterol uptake in Candida glabrata: Rescue of sterol auxotrophic strains

Cited by 48 publications

References 23 publications

Comparison of Sterol Import under Aerobic and Anaerobic Conditions in Three Fungal Species, Candida albicans, Candida glabrata, and Saccharomyces cerevisiae

Comparison of Sterol Import under Aerobic and Anaerobic Conditions in Three Fungal Species, Candida albicans, Candida glabrata, and Saccharomyces cerevisiae

Structural mechanism of ergosterol regulation by fungal sterol transcription factor Upc2

Protein‐facilitated transport of hydrophobic molecules across the yeast plasma membrane

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