Isolation of a Candida albicans gene, tightly linked to URA3, coding for a putative transcription factor that suppresses a Saccharomyces cerevisiae aft1 mutation

García, Micaela Gómez; O’Connor, José-Enrique; García, Lorena Latorre; Martínez, Sami Irar; Herrero, Enrique; Agudo, Lucas del Castillo

doi:10.1002/1097-0061(20010315)18:4<301::aid-yea672>3.3.co;2-8

Cited by 18 publications

(21 citation statements)

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“…For the virulence tests in mice, we included only those strains that allow optimal comparison, i.e., strains with and without a functional CMP1 copy, all of which contain one copy of the URA3 gene integrated in the same way. A comparison of the mutants with the wild-type strain SC5314 is less reliable, since the latter contains two copies of the URA3 gene and because the URA3 deletion in strain CAI4 also affects the flanking genes (17). Two independently constructed pairs of mutants and complemented strains, all derived at the same time from the same parent strain, produced identical results, providing convincing evidence that loss of virulence in the mutants was due to deletion of the CMP1 gene.…”

Section: Discussionmentioning

confidence: 99%

Calcineurin Is Essential for Virulence in Candida albicans

Bader

Bodendorfer²,

Schröppel³

et al. 2003

Infect Immun

110

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Calcineurin is a conserved Ca2؉ -calmodulin-activated, serine/threonine-specific protein phosphatase that regulates a variety of physiological processes, e.g., cell cycle progression, polarized growth, and adaptation to salt and alkaline pH stresses. In the pathogenic yeast Cryptococcus neoformans, calcineurin is also essential for growth at 37°C and virulence. To investigate whether calcineurin plays a role in the virulence of Candida albicans, the major fungal pathogen of humans, we constructed C. albicans mutants in which both alleles of the CMP1 gene, encoding the calcineurin catalytic subunit, were deleted. The C. albicans ⌬cmp1 mutants displayed hypersensitivity to elevated Na ؉ , Li ؉ , and Mn 2؉ concentrations and to alkaline pH, phenotypes that have been described after calcineurin inactivation in the related yeast Saccharomyces cerevisiae. Unlike S. cerevisiae calcineurin mutants, which exhibit reduced susceptibility to high Ca 2؉ concentrations, growth of C. albicans was inhibited in the presence of 300 mM CaCl 2 after the deletion of CMP1, demonstrating that there are also differences in calcineurin-mediated cellular responses between these two yeast species. In contrast to C. neoformans, inactivation of calcineurin did not cause temperature sensitivity in C. albicans. In addition, hyphal growth, an important virulence attribute of C. albicans, was not impaired in the ⌬cmp1 mutants under a variety of inducing conditions. Nevertheless, the virulence of the mutants was strongly attenuated in a mouse model of systemic candidiasis, demonstrating that calcineurin signaling is essential for virulence in C. albicans.

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Section: Discussionmentioning

confidence: 99%

Calcineurin Is Essential for Virulence in Candida albicans

Bader

Bodendorfer²,

Schröppel³

et al. 2003

Infect Immun

110

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“…IRO1 is related to AFT1 from S. cerevisiae, which is required for iron utilization (28,87). However, IRO1 is not an ortholog of AFT1, and its role in iron regulation in C. albicans is unclear (50).…”

Section: Induction Of Gene Expression By Hypoxiamentioning

confidence: 99%

Regulation of the Hypoxic Response in Candida albicans

et al. 2010

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The regulation of the response of Candida albicans to hypoxic (low-oxygen) conditions is poorly understood. We used microarray and other transcriptional analyses to investigate the role of the Upc2 and Bcr1 transcription factors in controlling expression of genes involved in cell wall metabolism, ergosterol synthesis, and glycolysis during adaptation to hypoxia. Hypoxic induction of the ergosterol pathway is mimicked by treatment with sterol-lowering drugs (ketoconazole) and requires UPC2. Expression of three members of the family CFEM (common in several fungal extracellular membranes) of cell wall genes (RBT5, PGA7, and PGA10) is also induced by hypoxia and ketoconazole and requires both UPC2 and BCR1. Expression of glycolytic genes is induced by hypoxia but not by treatment with sterol-lowering drugs, whereas expression of respiratory pathway genes is repressed. However, Upc2 does not play a major role in regulating expression of genes required for central carbon metabolism. Our results indicate that regulation of gene expression in response to hypoxia in C. albicans is complex and is signaled both via lowered sterol levels and other unstudied mechanisms. We also show that induction of filamentation under hypoxic conditions requires the Ras1-and Cdc35-dependent pathway.The human fungal pathogen Candida albicans grows on superficial and internal sites in the infected host, areas that differ significantly in the availability of oxygen (26). Under low-oxygen (hypoxic) conditions, C. albicans switches from yeast to hyphal growth, a phenotypic change that has been associated with invasion and virulence (24,30,54). Exposure to hypoxia results in increased expression of genes involved in ergosterol synthesis and glycolysis and reduced expression of oxidative phosphorylation (3, 69). There is also an increase in expression of some cell wall and hyphal-specific genes (69), which is reflected in changes in the cell wall proteome (72).Although the response to hypoxia has been well studied in fungi such as Saccharomyces cerevisiae and Schizosaccharomyces pombe, much less is known about the response in C. albicans. In S. pombe, a decrease in oxygen is detected by the reduction in sterol synthesis, which requires 12 molecules of oxygen to convert one squalene to ergosterol (38). Sterol content is sensed by Sre1 and Scp1, which are homologs of the human sterol regulatory element binding protein (SREBP) and Scap (SREBP cleavage-activating protein) (38, 77). Sre1 and Scp1 are localized in the membrane, where they remain when sterol and oxygen levels are high. When sterol levels drop, the N terminus of Sre1 is cleaved off, and it enters the nucleus, where it acts as a transcriptional regulator. Sre1 is the major regulator of the hypoxic response in S. pombe and regulates expression of Ͼ100 genes (38). It also functions in a sterol-independent manner (39). SREBPs are also important for sensing oxygen levels in the pathogenic fungi Cryptococcus neoformans and Aspergillus fumigatus (7,13,85).There are no obvious SREBP orthologs in...

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“…An FET3 homologue was also identified, but it was not relevant for virulence (9). The standard strain used for gene disruptions in C. albicans, CAI4, has been reported to have a deletion of a gene next to the URA3 locus, which is able to complement an S. cerevisiae aft1 mutation but whose function in iron metabolism in C. albicans is unclear (13). Some reports have described the production of siderophores, especially of the hydroxamate type, by C. albicans; however, the nature of such siderophores has not been elucidated (20,43).…”

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confidence: 99%

The Siderophore Iron Transporter ofCandida albicans(Sit1p/Arn1p) Mediates Uptake of Ferrichrome-Type Siderophores and Is Required for Epithelial Invasion

et al. 2002

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The human fungal pathogen Candida albicans contains a close homologue of yeast siderophore transporters, designated Sit1p/Arn1p. We have characterized the function of SIT1 in C. albicans by constructing sit1 deletion strains and testing their virulence and ability to utilize a range of siderophores and other iron complexes. sit1 mutant strains are defective in the uptake of ferrichrome-type siderophores including ferricrocin, ferrichrysin, ferrirubin, coprogen, and triacetylfusarinine C. A mutation of FTR1 did not impair the use of these siderophores but did affect the uptake of ferrioxamines E and B, as well as of ferric citrate, indicating that their utilization was independent of Sit1p. Hemin was a source of iron for both sit1 and ftr1 mutants, suggesting a pathway of hemin uptake distinct from that of siderophores and iron salts. Heterologous expression of SIT1 in the yeast Saccharomyces cerevisiae confirmed the function of Sit1p as a transporter for ferrichrome-type siderophores. The sit1 mutant was defective in infection of a reconstituted human epithelium as a model for human oral mucosa, while the SIT1 strain was invasive. In contrast, both sit1 and SIT1 strains were equally virulent in the mouse model of systemic infection. These results suggest that siderophore uptake by Sit1p/ Arn1p is required in a specific process of C. albicans infection, namely epithelial invasion and penetration, while in the blood or within organs other sources of iron, including heme, may be used.

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Isolation of a Candida albicans gene, tightly linked to URA3, coding for a putative transcription factor that suppresses a Saccharomyces cerevisiae aft1 mutation

Cited by 18 publications

References 0 publications

Calcineurin Is Essential for Virulence in Candida albicans

Calcineurin Is Essential for Virulence in Candida albicans

Regulation of the Hypoxic Response in Candida albicans

The Siderophore Iron Transporter ofCandida albicans(Sit1p/Arn1p) Mediates Uptake of Ferrichrome-Type Siderophores and Is Required for Epithelial Invasion

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