Genome-Wide Transcriptional Profiling of the Cyclic AMP-Dependent Signaling Pathway during Morphogenic Transitions of Candida albicans

Abstract

Candida albicans is an opportunistic human fungal pathogen that causes systemic candidiasis as well as superficial mucosal candidiasis. In response to the host environment, C. albicans transitions between yeast and hyphal forms. In particular, hyphal growth is important in facilitating adhesion and invasion of host tissues, concomitant with the expression of various hypha-specific virulence factors. In previous work, we showed that the cyclic AMP (cAMP) signaling pathway plays a crucial role in morphogenic transitions and virulence of C. albicans by studying genes encoding adenylate cyclase-associated protein ( Here, microarrays were probed with RNA from strains with hypoactive (cap1/cap1 null mutant), hyperactive (pde2/pde2 null mutant), and wild-type cAMP signaling pathways to provide insight into the molecular mechanisms of virulence that are regulated by cAMP and that are related to the morphogenesis of C. albicans. Genes controlling metabolic specialization, cell wall structure, ergosterol/lipid biosynthesis, and stress responses were modulated by cAMP during hypha formation. Phenotypic traits predicted to be regulated by cAMP from the profiling results correlated with the relative strengths of the mutants when tested for resistance to azoles and subjected to heat shock stress and oxidative/nitrosative stress. The results from this study provide important insights into the role of the cAMP signaling pathway not only in morphogenic transitions of C. albicans but also for adaptation to stress and for survival during host infections.

Farnesol Induces Hydrogen Peroxide Resistance in Candida albicans Yeast by Inhibiting the Ras-Cyclic AMP Signaling Pathway

“…To test this hypothesis, we measured the level of expression of CAT1 in response to 10 mM H 2 O 2 in WT and ras1/ras1 cells. Consistent with previous data (1,24), the level of CAT1 transcripts was higher in the ras1/ras1 than in the WT cells (Fig. 5B).…”

“…We have previously reported that farnesol inhibits Ras1-adenylate cyclase signaling, leading to the inhibition of hyphal growth (10). As the Ras-cAMP cascade represses the expression of OX stress response genes (1,24,66), we sought to test the hypothesis that farnesol-mediated inhibition of this pathway leads to the increased transcription of CAT1 and protection against ROS in yeast. To do this, we measured the effects of farnesol on ras1/ras1 and cyr1/cyr1 mutant survival after treatment with H 2 O 2 .…”

“…5A). Ras-cAMP mutants are thought to be more resistant to OX stress because of increased expression of OX stress response genes (1,24). Therefore, ras1/ras1 and cyr1/cyr1 cells may not respond to farnesol because CAT1 is maximally derepressed.…”

“…We previously reported that farnesol inhibits the Ras-cyclic AMP (cAMP)-protein kinase A (PKA) cascade, thereby inhibiting hyphal growth and inducing the expression of the catalase-encoding gene CAT1 (also called CTA1) (10). Although repression of the transcription of genes involved in stress response by the cAMP signaling pathway has been extensively documented (1,24,66), the mechanism for this repression is not yet well understood. In addition to farnesol effects on Ras1-Cyr1 signaling, Smith et al (61) showed the Hog1 mitogen-activated protein (MAP) kinase, which is involved in the response to high levels of OX stress by activating the transcription of stressrelated genes, was phosphorylated in the presence of farnesol (8,39).…”

Ras Signaling Gets Fine-Tuned: Regulation of Multiple Pathogenic Traits of Candida albicans

“…cAMP levels are also negatively regulated by a high-affinity phosphodiesterase, Pde2 (orf19.2972), and a low-affinity phosphodiesterase, Pde1 (orf19.4235), that increase the rate of cAMP break- down. Increased PDE2 expression in hyphae counteracts the Srv2-dependent synthesis of cAMP and limits filament formation (41), while loss-of-function mutations in PDE2 increase cAMP levels and lead to constitutive activation of the pathway and increased filament formation (42)(43)(44). Pde1 mediates repression of cAMP signaling in response to glucose and intracellular acidification (45).…”