Physiological adventures in Candida albicans: farnesol and ubiquinones

Abstract

SUMMARYFarnesol was first identified as a quorum-sensing molecule, which blocked the yeast to hyphal transition in Candida albicans, 22 years ago. However, its interactions with Candida biology are surprisingly complex. Exogenous (secreted or supplied) farnesol can also act as a virulence factor during pathogenesis and as a fungicidal agent triggering apoptosis in other competing fungi. Farnesol synthesis is turned off both during anaerobic growth and in opaque cells. Distinctly different cellular responses are observed as exogenous farnesol levels are increased from 0.1 to 100 µM. Reported changes include altered morphology, stress response, pathogenicity, antibiotic sensitivity/resistance, and even cell lysis. Throughout, there has been a dearth of mechanisms associated with these observations, in part due to the absence of accurate measurement of intracellular farnesol levels (F_i). This obstacle has recently been overcome, and the above phenomena can now be viewed in terms of changing F_i levels and the percentage of farnesol secreted. Critically, two aspects of isoprenoid metabolism present in higher organisms are absent in C. albicans and likely in other yeasts. These are pathways for farnesol salvage (converting farnesol to farnesyl pyrophosphate) and farnesylcysteine cleavage, a necessary step in the turnover of farnesylated proteins. Together, these developments suggest a unifying model, whereby high, threshold levels of F_i regulate which target proteins are farnesylated or the extent to which they are farnesylated. Thus, we suggest that the diversity of cellular responses to farnesol reflects the diversity of the proteins that are or are not farnesylated.

Keywords: Candida albicans; farnesol; fungal dimorphism; fusel alcohols; holdase chaperones; mRPMI 1640; protein farnesylation; quorum sensing.

Fig 1

Key results from the last 22 years of research into farnesol function and synthesis in Candida albicans leading to five major hypotheses for farnesol function and synthesis, and six outstanding questions. This summary is an incomplete list of the research on farnesol and C. albicans. Instead, it represents the authors’ views of the key findings in the field. References for the key findings are in superscript. See references , , , , .

Fig 2

Graphic abstract of the gas chromatography (GC) assay for farnesol and the aromatic fusel alcohols. (Modified from reference .)

Fig 3

Farnesyl pyrophosphate (FPP) as a metabolic branch point. Percent values for sterols, dolichol, ubiquinone, and prenylated proteins are mammalian estimates (47, 54). Letters indicate inhibitor targets (A/ statins, B/ SQAD (4-[4-(4-methoxybenzoyl)piperizino] butylidene-1, 1-phosphonic acid tetra ester) and zaragozic acid, C/terbinafine, and D/ azoles) or potential inhibitor targets (E/ glyphosate, F/ the three membrane-bound pyrophosphatases encoded by DPP1, DPP2, and DPP3, and G/ prephenate dehydratase and prephenate dehydrogenase to phenethyl alcohol and tyrosol, respectively). Dotted arrows represent pathways that appear to be absent in C. albicans [farnesol salvage (farnesol to FPP) and farnesylcysteine lyase] or are still hypothetical (farnesylcysteine excretion).

Fig 4

A unifying model on farnesol’s mode of action incorporating protein farnesylation, heat shock proteins acting as “holdase” chaperones, and threshold levels of internal farnesol (F_i) selectively blocking farnesylation. The model assumes that C. albicans lacks both farnesol salvage (farnesol to FPP) and mechanisms for cleavage of farnesylcysteine. It does not specify which heat shock protein acts to make the –CAAX cysteine available for farnesylation.