Upc2p‐associated differential protein expression in <i>Candida albicans</i>

Hoehamer, Christopher F.; Cummings, Edwin D.; Hilliard, George M.; Morschhäuser, Joachim; Rogers, P. David

doi:10.1002/pmic.200900176

Cited by 8 publications

(4 citation statements)

References 19 publications

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“…The exact biochemical role of Goa1 remains obscure, but a GOA1 gene deletion confers oxidative stress sensitivity and results in the loss of mitochondrial membrane potential ( 65 ). In addition to its roles in the regulation of ergosterol biosynthesis, the transcription factor Upc2 regulates the expression of essential mitochondrial chaperones, mediates lipid homeostasis, and contributes to the hypoxic response in C. albicans ( 33 , 35 , 66 – 68 ). Hypoxia-induced β-glucan masking was blocked in C. albicans goa1 Δ and upc2 Δ mutants ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Hypoxia Promotes Immune Evasion by Triggering β-Glucan Masking on the Candida albicans Cell Surface via Mitochondrial and cAMP-Protein Kinase A Signaling

Pradhan

Avelar

Bain

et al. 2018

mBio

109

142

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Animal, plant, and fungal cells occupy environments that impose changes in oxygen tension. Consequently, many species have evolved mechanisms that permit robust adaptation to these changes. The fungal pathogen Candida albicans can colonize hypoxic (low oxygen) niches in its human host, such as the lower gastrointestinal tract and inflamed tissues, but to colonize its host, the fungus must also evade local immune defenses. We reveal, for the first time, a defined link between hypoxic adaptation and immune evasion in C. albicans. As this pathogen adapts to hypoxia, it undergoes changes in cell wall structure that include masking of β-glucan at its cell surface, and it becomes better able to evade phagocytosis by innate immune cells. We also define the signaling mechanisms that mediate hypoxia-induced β-glucan masking, showing that they are dependent on mitochondrial signaling and the cAMP-protein kinase pathway. Therefore, hypoxia appears to trigger immune evasion in this fungal pathogen.

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Section: Resultsmentioning

confidence: 99%

Hypoxia Promotes Immune Evasion by Triggering β-Glucan Masking on the Candida albicans Cell Surface via Mitochondrial and cAMP-Protein Kinase A Signaling

Pradhan

Avelar

Bain

et al. 2018

mBio

109

142

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“…Our data demonstrate that increased protein abundance accompanies the increased transcription of these genes in response to azole treatment. Interestingly, the increased abundance of both Erg6p and Erg10p has also been observed in azole-resistant clinical isolates of C. albicans (14,15) as well as a laboratory-derived fluconazole-resistant strain of C. albicans produced after exposure to fluconazole (49). In one isolate, the increased abundance of these proteins was due to a G648D amino acid substitution in the transcription factor Upc2p.…”

Section: Discussionmentioning

confidence: 96%

Changes in the Proteome of Candida albicans in Response to Azole, Polyene, and Echinocandin Antifungal Agents

Hoehamer

Cummings

Hilliard

et al. 2010

Antimicrob Agents Chemother

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The yeast Candida albicans is an opportunistic human fungal pathogen and the cause of superficial and systemic infections in immunocompromised patients. The classes of antifungal agents most commonly used to treat Candida infections are the azoles, polyenes, and echinocandins. In the present study, we identified changes in C. albicans protein abundance using two-dimensional polyacrylamide gel electrophoresis and matrix-assisted laser desorption ionization-time of flight mass spectroscopy following exposure to representatives of the azole (ketoconazole), polyene (amphotericin B), and echinocandin (caspofungin) antifungals in an effort to elucidate the adaptive responses to these classes of antifungal agents. We identified 39 proteins whose abundance changed in response to ketoconazole exposure. Some of these proteins are involved in ergosterol biosynthesis and are associated with azole resistance. Exposure to amphotericin B altered the abundance of 43 proteins, including those associated with oxidative stress and osmotic tolerance. We identified 50 proteins whose abundance changed after exposure to caspofungin, including enzymes involved in cell wall biosynthesis and integrity, as well as the regulator of ␤-1,3-glucan synthase activity, Rho1p. Exposure to caspofungin also increased the abundance of the proteins involved in oxidative and osmotic stress. The common adaptive responses shared by all three antifungal agents included proteins involved in carbohydrate metabolism. Some of these antifungal-responsive proteins may represent potential targets for the development of novel therapeutics that could enhance the antifungal activities of these drugs.

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“…C. albicans UPC2 (CaUPC2) is required for expression of the ergosterol biosynthesis pathway in hypoxia and for the response to azole drugs (53,61,70). Deletion of UPC2 does not reduce expression of ergosterol synthesis genes in normoxia (25,53,70), whereas gain-of-function mutations result in higher expression (25,33,35). Like ScUpc2, CaUpc2 binds an SRE in the promoters of the majority of the ergosterol synthesis genes (25,61,70,91).…”

mentioning

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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Upc2p‐associated differential protein expression in Candida albicans

Cited by 8 publications

References 19 publications

Hypoxia Promotes Immune Evasion by Triggering β-Glucan Masking on the Candida albicans Cell Surface via Mitochondrial and cAMP-Protein Kinase A Signaling

Hypoxia Promotes Immune Evasion by Triggering β-Glucan Masking on the Candida albicans Cell Surface via Mitochondrial and cAMP-Protein Kinase A Signaling

Changes in the Proteome of Candida albicans in Response to Azole, Polyene, and Echinocandin Antifungal Agents

Regulation of the Hypoxic Response in Candida albicans

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