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Background  Hyphal growth and multidrug resistance of  C. albicans  are important features for virulence and antifungal therapy of this pathogenic fungus.    Methodology/Principal Findings  Here 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 age3 Δ 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  age3 Δ cells shows a wild-type-like polarization pattern of the actin cytoskeleton and lipid rafts. Moreover,  age3 Δ 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  age3 Δ mutant cells contained similar amounts of Cdr1p, Cdr2p and Mdr1p.    Conclusions/Significance  The results indicate that the defect in sustaining filament elongation is probably caused by the failure of  age3 Δ cells to polarize the actin cytoskeleton and possibly of inefficient endocytosis. The high susceptibility of  age3 Δ cells to azoles is not caused by inefficient transport of efflux pumps to the cell membrane. A possible role of a vacuolar defect of  age3 Δ 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.

Candida albicans AGE3, the Ortholog of the S. cerevisiae ARF-GAP-Encoding Gene GCS1, Is Required for Hyphal Growth and Drug Resistance