Unknown,Transcriptomics,Genomics,Proteomics

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Conjugated linoleic acid inhibits hyphal growth in Candida albicans by modulating Ras1 cellular levels and down-regulating TEC1 expression

ABSTRACT: The polymorphic yeast Candida albicans exists in blastospore and filamentous forms. The switch from one morphological state to the other coincides with the expression of virulence factors, which makes the yeast-to-hypha transition an attractive target for the development of new antifungal agents. Because an untapped therapeutic potential resides in small molecules that hinder C. albicans filamentation, we characterized the inhibitory effect of conjugated linoleic acid (CLA) on hyphal growth and addressed its mechanism of action. CLA inhibited hyphal growth in a dose-dependent fashion, in both liquid- and solid-inducing media. The fatty acid blocked germ tube formation and impeded hyphal elongation. Global transcriptional profiling revealed that CLA downregulated the expression of hypha-specific genes and abrogated the induction of several morphogenesis regulators, including RAS1, TEC1 and UME6. CLAM-bM-^@M-^Ys repressive effect on TEC1 expression was Ras1-dependent, but Efg1-independent. CLA treatment resulted in the delocalization of Ras1 and its degradation, resulting in the downregulation of the Ras1-cAMP-PKA signaling pathway. This study provides the biological and molecular explanations that underlie CLAM-bM-^@M-^Ys ability to inhibit hyphal growth in C. albicans. Two-color experimental design that consistently used growth in Spider Media at 30M-bM-^DM-^C as the control. We tested the effect of high temperature as well as the effect of adding 100 mM-BM-5 CLA at either low or high temperature. RNA from each replicate came from independent cultures.

ORGANISM(S): Candida albicans

SUBMITTER: Andre Nantel

PROVIDER: E-GEOD-25822 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Conjugated linoleic acid inhibits hyphal growth in Candida albicans by modulating Ras1p cellular levels and downregulating TEC1 expression.

Shareck Julie J Nantel André A Belhumeur Pierre P

Eukaryotic cell 20110225 4

The polymorphic yeast Candida albicans exists in yeast and filamentous forms. Given that the morphogenetic switch coincides with the expression of many virulence factors, the yeast-to-hypha transition constitutes an attractive target for the development of new antifungal agents. Since an untapped therapeutic potential resides in small molecules that hinder C. albicans filamentation, we characterized the inhibitory effect of conjugated linoleic acid (CLA) on hyphal growth and addressed its mechan ...[more]

PMID: 21357478

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Project description:Sfl1p and Sfl2p are two homologous heat shock factor-type transcriptional regulators that antagonistically control morphogenesis in Candida albicans, while being required for full pathogenesis and virulence. To understand how Sfl1p and Sfl2p exert their function, we combined genome-wide location and expression analyses to reveal their transcriptional targets in vivo together with the associated changes of the C. albicans transcriptome. We show that Sfl1p and Sfl2p bind to the promoter of at least 113 common targets through divergent binding motifs and modulate directly the expression of key transcriptional regulators of C. albicans morphogenesis and/or virulence. Surprisingly, we found that Sfl2p additionally binds to the promoter of 75 specific targets, including a high proportion of hyphal-specific genes (HSGs; HWP1, HYR1, ECE1, others), revealing a direct link between Sfl2p and hyphal development. Data mining pointed to a regulatory network in which Sfl1p and Sfl2p act as both transcriptional activators and repressors. Sfl1p directly represses the expression of positive regulators of hyphal growth (BRG1, UME6, TEC1, SFL2), while upregulating both yeast form-associated genes (RME1, RHD1,YWP1) and repressors of morphogenesis (SSN6, NRG1). On the other hand, Sfl2p directly upregulates HSGs and activators of hyphal growth (UME6, TEC1), while downregulating yeast form-associated genes and repressors of morphogenesis (NRG1, RFG1, SFL1). Using genetic interaction analyses, we provide further evidences that Sfl1p and Sfl2p antagonistically control C. albicans morphogenesis through direct modulation of the expression of important regulators of hyphal growth. Bioinformatic analyses suggest that binding of Sfl1p and Sfl2p to their targets occurs with the co-binding of Efg1p and/or Ndt80p. Indeed, we show that Sfl1p and Sfl2p targets are bound by Efg1p and that both Sfl1p and Sfl2p associate in vivo with Efg1p. Taken together, our data suggest that Sfl1p and Sfl2p act as central M-bM-^@M-^\switch on/offM-bM-^@M-^] proteins to coordinate the regulation of C. albicans morphogenesis. ChIP was performed in 2 independently grown C. albicans sfl1 or sfl2 homozygous mutant strains expressing (sfl1-CaEXP-SFL1-HA or sfl2-CaEXP-SFL2-HA, respectively) or not (sfl1-CaEXP or sfl2-CaEXP, respectively) SFL1-HA or SFL2-HA (-HA, 3'-triple-HA-tagged alleles of SFL1 or SFL2) under the control of a methionine-repressible promoter (Total samples = 8; 2xCaEXP-SFL1-HA, 2xCaEXP-SFL2-HA, 2xCaEXP control for SFL1-HA ChIP and 2xCaEXP control for SFL2-HA ChIP).

Project description:Sfl1p and Sfl2p are two homologous heat shock factor-type transcriptional regulators that antagonistically control morphogenesis in Candida albicans, while being required for full pathogenesis and virulence. To understand how Sfl1p and Sfl2p exert their function, we combined genome-wide location and expression analyses to reveal their transcriptional targets in vivo together with the associated changes of the C. albicans transcriptome. We show that Sfl1p and Sfl2p bind to the promoter of at least 113 common targets through divergent binding motifs and modulate directly the expression of key transcriptional regulators of C. albicans morphogenesis and/or virulence. Surprisingly, we found that Sfl2p additionally binds to the promoter of 75 specific targets, including a high proportion of hyphal-specific genes (HSGs; HWP1, HYR1, ECE1, others), revealing a direct link between Sfl2p and hyphal development. Data mining pointed to a regulatory network in which Sfl1p and Sfl2p act as both transcriptional activators and repressors. Sfl1p directly represses the expression of positive regulators of hyphal growth (BRG1, UME6, TEC1, SFL2), while upregulating both yeast form-associated genes (RME1, RHD1,YWP1) and repressors of morphogenesis (SSN6, NRG1). On the other hand, Sfl2p directly upregulates HSGs and activators of hyphal growth (UME6, TEC1), while downregulating yeast form-associated genes and repressors of morphogenesis (NRG1, RFG1, SFL1). Using genetic interaction analyses, we provide further evidences that Sfl1p and Sfl2p antagonistically control C. albicans morphogenesis through direct modulation of the expression of important regulators of hyphal growth. Bioinformatic analyses suggest that binding of Sfl1p and Sfl2p to their targets occurs with the co-binding of Efg1p and/or Ndt80p. Indeed, we show that Sfl1p and Sfl2p targets are bound by Efg1p and that both Sfl1p and Sfl2p associate in vivo with Efg1p. Taken together, our data suggest that Sfl1p and Sfl2p act as central “switch on/off” proteins to coordinate the regulation of C. albicans morphogenesis.

Dataset Information

Conjugated linoleic acid inhibits hyphal growth in Candida albicans by modulating Ras1 cellular levels and down-regulating TEC1 expression

Publications

Conjugated linoleic acid inhibits hyphal growth in Candida albicans by modulating Ras1p cellular levels and downregulating TEC1 expression.

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