Conjugated Linoleic Acid Inhibits Hyphal Growth in Candida albicans by Modulating Ras1p Cellular Levels and Downregulating TEC1 Expression

Shareck, Julie; Nantel, André; Belhumeur, Pierre

doi:10.1128/ec.00305-10

Cited by 34 publications

(23 citation statements)

References 94 publications

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“…In this report, we provide the first demonstration that GFPRas1 is functional in C. albicans and confirm that it is localized at the plasma membrane in C. albicans yeast (64,77). We show that Ras1 also localizes to the plasma membranes of hyphae with no detectable areas of enrichment.…”

supporting

confidence: 71%

“…Farnesol blocks filamentation without altering Ras1 plasma membrane distribution. Farnesol, an autoregulatory molecule with structural similarity to the farnesyl molecule that modifies Ras proteins, inhibits Ras1-dependent cAMP signaling in both yeast and hyphae (10,13), and recent work by Shareck et al (64) showed that conjugated linoleic acid inhibited the yeastto-hypha transition and concomitantly led to a decrease in plasma membrane-associated GFP-Ras1 in treated cells. Therefore, we sought to determine if farnesol alters the plasma membrane association of Ras1.…”

Section: Vol 10 2011mentioning

confidence: 99%

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Roles of Ras1 Membrane Localization during Candida albicans Hyphal Growth and Farnesol Response

et al. 2011

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Many Ras GTPases localize to membranes via C-terminal farnesylation and palmitoylation, and localization regulates function. In Candida albicans, a fungal pathogen of humans, Ras1 links environmental cues to morphogenesis. Here, we report the localization and membrane dynamics of Ras1, and we characterize the roles of conserved C-terminal cysteine residues, C287 and C288, which are predicted sites of palmitoylation and farnesylation, respectively. GFP-Ras1 is localized uniformly to plasma membranes in both yeast and hyphae, yet Ras1 plasma membrane mobility was reduced in hyphae compared to that in yeast. Ras1-C288S was mislocalized to the cytoplasm and could not support hyphal development. Ras1-C287S was present primarily on endomembranes, and strains expressing ras1-C287S were delayed or defective in hyphal induction depending on the medium used. Cells bearing constitutively activated Ras1-C287S or Ras1-C288S, due to a G13V substitution, showed increased filamentation, suggesting that lipid modifications are differentially important for Ras1 activation and effector interactions. The C. albicans autoregulatory molecule, farnesol, inhibits Ras1 signaling through adenylate cyclase and bears structural similarities to the farnesyl molecule that modifies Ras1. At lower concentrations of farnesol, hyphal growth was inhibited but Ras1 plasma membrane association was not altered; higher concentrations of farnesol led to mislocalization of Ras1 and another G protein, Rac1. Furthermore, farnesol inhibited hyphal growth mediated by cytosolic Ras1-C288SG13V, suggesting that farnesol does not act through mechanisms that depend on Ras1 farnesylation. Our findings imply that Ras1 is farnesylated and palmitoylated, and that the Ras1 stimulation of adenylate cyclase-dependent phenotypes can occur in the absence of these lipid modifications.

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supporting

confidence: 71%

Section: Vol 10 2011mentioning

confidence: 99%

Roles of Ras1 Membrane Localization during Candida albicans Hyphal Growth and Farnesol Response

et al. 2011

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“…Coincubation of OSIP108 with 25 g/ml RsAFP2 increased the BIC-2 of OSIP108 from 5 M to 19 M. Moreover, coincubation of OSIP108 with 50 and 100 g/ml RsAFP2 totally abolished its antibiofilm activity (BIC-2, Ͼ100 M). Likewise, another synthetic yeast-to-hypha inhibitor, conjugated linoleic acid (CLA) (65), had an antagonistic effect on the antibiofilm activity of OSIP108. Although coincubation of 100 M CLA with a concentration series of OSIP108 did not change the BIC-2 value of OSIP108, a 7-fold increase in the OSIP108 concentration necessary to reduce biofilm formation by 80% was observed in the presence of 100 M CLA (data not shown).…”

Section: Resultsmentioning

confidence: 99%

Plant-Derived Decapeptide OSIP108 Interferes with Candida albicans Biofilm Formation without Affecting Cell Viability

Delattin

Brucker

Craik

et al. 2014

Antimicrob Agents Chemother

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We previously identified a decapeptide from the model plant Arabidopsis thaliana, OSIP108, which is induced upon fungal pathogen infection. In this study, we demonstrated that OSIP108 interferes with biofilm formation of the fungal pathogen Candida albicans without affecting the viability or growth of C. albicans cells. OSIP108 displayed no cytotoxicity against various human cell lines. Furthermore, OSIP108 enhanced the activity of the antifungal agents amphotericin B and caspofungin in vitro and in vivo in a Caenorhabditis elegans-C. albicans biofilm infection model. These data point to the potential use of OSIP108 in combination therapy with conventional antifungal agents. In a first attempt to unravel its mode of action, we screened a library of 137 homozygous C. albicans mutants, affected in genes encoding cell wall proteins or transcription factors important for biofilm formation, for altered OSIP108 sensitivity. We identified 9 OSIP108-tolerant C. albicans mutants that were defective in either components important for cell wall integrity or the yeast-to-hypha transition. In line with these findings, we demonstrated that OSIP108 activates the C. albicans cell wall integrity pathway and that its antibiofilm activity can be blocked by compounds inhibiting the yeast-to-hypha transition. Furthermore, we found that OSIP108 is predominantly localized at the C. albicans cell surface. These data point to interference of OSIP108 with cell wall-related processes of C. albicans, resulting in impaired biofilm formation.

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“…Unlike other fatty acids such as butyric, capric, lauric, palmitoleic, oleic, linoleic, and undecylenic acids (reviewed in reference 42), 6-NDA did not appear to inhibit yeast-to-hypha transition under the experimental conditions used in our study, since short hyphal filaments were visible in the majority of cells in each of the 6-NDA-treated samples. Thus, it is possible that 6-NDA inhibits hyphal elongation as has been observed for conjugated linoleic acid and caprylic acid (28,43). Since inhibitors of hyphal growth such as farnesol and nisin Z have been shown to give a protective effect in mucosal candidiasis (reviewed in reference 42), the hyphal inhibitory activity of 6-NDA would be useful in clearing superficial Candida infections.…”

Section: Figmentioning

confidence: 97%

A Potent Plant-Derived Antifungal Acetylenic Acid Mediates Its Activity by Interfering with Fatty Acid Homeostasis

Tripathi

Feng

et al. 2012

Antimicrob Agents Chemother

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c 6-Nonadecynoic acid (6-NDA), a plant-derived acetylenic acid, exhibits strong inhibitory activity against the human fungal pathogens Candida albicans, Aspergillus fumigatus, and Trichophyton mentagrophytes. In the present study, transcriptional profiling coupled with mutant and biochemical analyses were conducted using the model yeast Saccharomyces cerevisiae to investigate its mechanism of action. 6-NDA elicited a transcriptome response indicative of fatty acid stress, altering the expression of genes that are required for yeast growth in the presence of oleate. Mutants of S. cerevisiae lacking transcription factors that regulate fatty acid ␤-oxidation showed increased sensitivity to 6-NDA. Fatty acid profile analysis indicated that 6-NDA inhibited the formation of fatty acids longer than 14 carbons in length. In addition, the growth inhibitory effect of 6-NDA was rescued in the presence of exogenously supplied oleate. To investigate the response of a pathogenic fungal species to 6-NDA, transcriptional profiling and biochemical analyses were also conducted in C. albicans. The transcriptional response and fatty acid profile of C. albicans were comparable to those obtained in S. cerevisiae, and the rescue of growth inhibition with exogenous oleate was also observed in C. albicans. In a fluconazole-resistant clinical isolate of C. albicans, a fungicidal effect was produced when fluconazole was combined with 6-NDA. In hyphal growth assays, 6-NDA inhibited the formation of long hyphal filaments in C. albicans. Collectively, our results indicate that the antifungal activity of 6-NDA is mediated by a disruption in fatty acid homeostasis and that 6-NDA has potential utility in the treatment of superficial Candida infections.

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Conjugated Linoleic Acid Inhibits Hyphal Growth in Candida albicans by Modulating Ras1p Cellular Levels and Downregulating TEC1 Expression

Cited by 34 publications

References 94 publications

Roles of Ras1 Membrane Localization during Candida albicans Hyphal Growth and Farnesol Response

Roles of Ras1 Membrane Localization during Candida albicans Hyphal Growth and Farnesol Response

Plant-Derived Decapeptide OSIP108 Interferes with Candida albicans Biofilm Formation without Affecting Cell Viability

A Potent Plant-Derived Antifungal Acetylenic Acid Mediates Its Activity by Interfering with Fatty Acid Homeostasis

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