Farnesol and dodecanol effects on the Candida albicans Ras1‐cAMP signalling pathway and the regulation of morphogenesis

Abstract

SummaryCandida albicans hypha formation which has been stimulated via the Ras1-cAMP-Efg1 signalling cascade is inhibited by farnesol, a C. albicans autoregulatory factor, and small molecules such as dodecanol. In cultures containing farnesol or dodecanol, hypha formation was restored upon addition of dibutyryl-cAMP. The CAI4-Ras1 G13V strain, which carries a dominantactive variant of Ras1 and forms hyphae in the absence of inducing stimuli, grew as yeast in medium with farnesol or dodecanol; the heat shock sensitivity of the CAI4-Ras1 G13V strain was also suppressed by these compounds. Neither Pde1 nor Pde2 was necessary for the repression of hyphal growth by farnesol or dodecanol. Two transcripts, CTA1 and HSP12, which are at higher levels upon mutation of Ras1 or Cdc35, were increased in abundance in cells grown with farnesol or dodecanol. Microscopic analysis of strains carrying CTA1 and HWP1 promoter fusions grown with intermediate concentrations of farnesol or dodecanol indicated a link between cells with the increased expression of cAMP-repressed genes and cells repressed for hypha formation. Because several cAMPcontrolled outputs are affected by farnesol and dodecanol, our findings suggest that these compounds impact activity of the Ras1-Cdc35 pathway, thus leading to an alteration of C. albicans morphology.

Transcription factor Efg1 contributes to the tolerance of Candida albicans biofilms against antifungal agents in vitro and in vivo

“…The C. albicans homozygous deletion mutants used in this study were affected in genes encoding the class III adenylyl cyclase (Dcdc35), RAS signal transduction GTPase (Dras1), cyclic nucleotide phosphodiesterase 1 (Dpde1) and 2 (Dpde2), and enhanced filamentous growth transcriptional factor (Defg1) (Davis-Hanna et al, 2008). A second set of C. albicans mutants consisted of Defg1 (HLC52), the reintegrant Defg1(EFG1) (HLC74), and the corresponding wild-type (WT) CAF2 (Lo et al, 1997).…”

“…We first analysed the miconazole sensitivity of planktonic and biofilm cells of C. albicans homozygous null mutants affected in genes involved in the cAMP signalling pathway, namely Dcdc35, Dras1, Dpde1, Dpde2, Defg1, and the corresponding isogenic WT strain CAF2 (Davis-Hanna et al, 2008). Susceptibility testing and determination of MIC 50 were performed according the NCCLS M27-A3 protocol (CLSI, 2008) for planktonic C. albicans cultures.…”

Fungal Morphogenesis

“…At concentrations of 10-250 mM, farnesol inhibits hyphal initiation, but it does not suppress hyphal elongation (Mosel et al 2005). Farnesol is reported to exert its inhibitory effects on germ-tube formation through Ras1-Cyr1 (Davis-Hanna et al 2008). The release from farnesol inhibition when cells are inoculated from dense cultures into fresh media is essential for Nrg1 degradation, which requires the kinase Sok1 (Lu et al 2014).…”

A comprehensive functional portrait of two heat shock factor-type transcriptional regulators involved in Candida albicans morphogenesis and virulence

“…The yeast-to-hyphae transition is triggered by a variety of environmental stimuli including nutrient availability, temperature, pH, CO 2 and serum [9][10][11][12][13]. This process correlates with the coordinated expression of a set of hyphal-specific genes (HSGs) with roles in orchestrating hyphal development.…”