Cdc24, the GDP-GTP exchange factor for Cdc42, is required for invasive hyphal growth of Candida albicans.
Candida albicans, the most common human fungal pathogen, is particularly problematic for immunocompromised individuals. The reversible transition of this fungal pathogen to a filamentous form that invades host tissue is important for its virulence. Although different signaling pathways such as a mitogen-activated protein kinase and a protein kinase A cascade are critical for this morphological transition, the function of polarity establishment proteins in this process has not been determined. We examined the role of four different polarity establishment proteins in C. albicans invasive growth and virulence by using strains in which one copy of each gene was deleted and the other copy expressed behind the regulatable promoter MET3. Strikingly, mutants with ectopic expression of either the Rho G-protein Cdc42 or its exchange factor Cdc24 are unable to form invasive hyphal filaments and germ tubes in response to serum or elevated temperature and yet grow normally as a budding yeast. Furthermore, these mutants are avirulent in a mouse model for systemic infection. This function of the Cdc42 GTPase module is not simply a general feature of polarity establishment proteins. Mutants with ectopic expression of the SH3 domain containing protein Bem1 or the Ras-like G-protein Bud1 can grow in an invasive fashion and are virulent in mice, albeit with reduced efficiency. These results indicate that a specific regulation of Cdc24/Cdc42 activity is required for invasive hyphal growth and suggest that these proteins are required for pathogenicity of C. albicans.
Bassilana
Martine
M
Institute of Signaling, Developmental Biology, and Cancer, UMR 6543 Centre National de la Recherche Scientifique, University of Nice, 06108 Nice, France.
Blyth
James
J
Arkowitz
Robert A
RA
D000818:Animals; D002176:Candida albicans / Q000201:enzymology* / Q000254:growth & development* / Q000472:pathogenicity; D002177:Candidiasis / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D016764:Cell Polarity / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D020549:GTP Phosphohydrolase Activators / Q000378:metabolism; D020558:GTP Phosphohydrolases; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D006153:Guanosine Diphosphate / Q000235:genetics / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000235:genetics / Q000378:metabolism; D025301:Hyphae / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains / Q000382:microbiology; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D020846:cdc42 GTP-Binding Protein, Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*
C466987:BEM1 protein, Candida albicans; C083102:BUD2 protein, S cerevisiae; C073594:CDC24 protein, S cerevisiae; D018797:Cell Cycle Proteins; D005656:Fungal Proteins; D020549:GTP Phosphohydrolase Activators; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D011518:Proto-Oncogene Proteins; D029701:Saccharomyces cerevisiae Proteins; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D020558:GTP Phosphohydrolases; D020846:cdc42 GTP-Binding Protein, Saccharomyces cerevisiae