Abstract
BackgroundHyphal growth and multidrug resistance of C. albicans are important features for virulence and antifungal therapy of this pathogenic fungus.Methodology/Principal FindingsHere we show by phenotypic complementation analysis that the C. albicans gene AGE3 is the functional ortholog of the yeast ARF-GAP-encoding gene GCS1. The finding that the gene is required for efficient endocytosis points to an important functional role of Age3p in endosomal compartments. Most C. albicans age3Δ mutant cells which grew as cell clusters under yeast growth conditions showed defects in filamentation under different hyphal growth conditions and were almost completely disabled for invasive filamentous growth. Under hyphal growth conditions only a fraction of age3Δ cells shows a wild-type-like polarization pattern of the actin cytoskeleton and lipid rafts. Moreover, age3Δ cells were highly susceptible to several unrelated toxic compounds including antifungal azole drugs. Irrespective of the AGE3 genotype, C-terminal fusions of GFP to the drug efflux pumps Cdr1p and Mdr1p were predominantly localized in the plasma membrane. Moreover, the plasma membranes of wild-type and age3Δ mutant cells contained similar amounts of Cdr1p, Cdr2p and Mdr1p.Conclusions/SignificanceThe results indicate that the defect in sustaining filament elongation is probably caused by the failure of age3Δ cells to polarize the actin cytoskeleton and possibly of inefficient endocytosis. The high susceptibility of age3Δ cells to azoles is not caused by inefficient transport of efflux pumps to the cell membrane. A possible role of a vacuolar defect of age3Δ cells in drug susceptibility is proposed and discussed. In conclusion, our study shows that the ARF-GAP Age3p is required for hyphal growth which is an important virulence factor of C. albicans and essential for detoxification of azole drugs which are routinely used for antifungal therapy. Thus, it represents a promising antifungal drug target.
Highlights
Candida albicans is one of the most prevalent human fungal pathogens
Conclusions/Significance: The results indicate that the defect in sustaining filament elongation is probably caused by the failure of age3D cells to polarize the actin cytoskeleton and possibly of inefficient endocytosis
In this paper we describe the phenotypic and physiological consequences of deleting the AGE3 gene from the C. albicans genome
Summary
Depending on environmental conditions it is able to grow in several distinct cell forms, such as yeast cells, different pseudohyphal forms and true hyphae [1,2]. Apart from other properties of C. albicans [3] hyphal development strongly contributes to its success as a pathogen [4]. Hyphae formation starts from a yeast-form cell (blastospore) by forming a germ tube which elongates until the first cell division. Germ tube formation and hyphal elongation are the result of polarized growth [10]. The latter depends on the polarization of the actin cytoskeleton [11,12,13,14]. Several other hyphae-specific structures or properties depend on the polarized actin cytoskeleton. Hyphal growth and multidrug resistance of C. albicans are important features for virulence and antifungal therapy of this pathogenic fungus
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