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Research Database PMU-SQQUID

Candida albicans AGE3, the Ortholog of the S. cerevisiae ARF-GAP-Encoding Gene GCS1, Is Required for Hyphal Growth and Drug Resistance
Lettner, T; Zeidler, U; Gimona, M; Hauser, M; Breitenbach, M; Bito, A
PLOS ONE. 2010; 5(8): e11993
Originalarbeiten (Zeitschrift)

PMU-Authors

Gimona Mario
Lettner Thomas

Abstract

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 Delta 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 Delta cells shows a wild-type-like polarization pattern of the actin cytoskeleton and lipid rafts. Moreover, age3 Delta 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 Delta 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 Delta cells to polarize the actin cytoskeleton and possibly of inefficient endocytosis. The high susceptibility of age3 Delta 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 Delta 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.


Useful keywords (using NLM MeSH Indexing)

Actin Cytoskeleton/metabolism

Antifungal Agents/pharmacology

Azoles/pharmacology

Candida albicans/cytology

Candida albicans/genetics

Candida albicans/growth*

development*

Candida albicans/physiology

Cytoskeleton/metabolism

DNA-Binding Proteins/genetics*

Drug Resistance, Fungal*/genetics

Endocytosis/genetics

Fungal Proteins/genetics

Fungal Proteins/metabolism*

GTPase-Activating Proteins/genetics*

Gene Deletion

Gene Expression Regulation, Fungal

Genome, Fungal/genetics

Glucan Endo-1,3-beta-D-Glucosidase/metabolism

Hyphae/cytology

Hyphae/genetics

Hyphae/growth*

development*

Hyphae/physiology

Membrane Microdomains/metabolism

Membrane Transport Proteins/metabolism

Mutation

Protein Transport

Saccharomyces cerevisiae/genetics*

Saccharomyces cerevisiae Proteins/genetics*

Sequence Homology, Nucleic Acid*