Cdc24, the GDP-GTP Exchange Factor for Cdc42, Is Required for Invasive Hyphal Growth of Candida albicans

Abstract

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.

Polarity proteins Bem1 and Cdc24 are components of the filamentous fungal NADPH oxidase complex

“…PCR screening of 212 hygromycin resistant cdc24 transformants failed to identify a replacement mutant. Given cdc24 mutants of U. maydis and Candida albicans are unviable (20,21), it is likely that deletion of this gene in E. festucae is also lethal.…”

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

“…Furthermore, Ras1 has been shown to be upstream of both the cAMP-PKA and MAPK pathways (179,342). Downstream of Ras1 in the MAPK module is the Rhotype GTPase Cdc42 and its GEF protein Cdc24, which are important for invasive hyphal growth as well as polarized growth in both yeast and hyphal cells (43,595). Signaling from Cdc42 to its downstream effectors is required for morphogenesis under various conditions (311,313,569).…”

Fungal Morphogenesis

“…As in other fungi, the Ras1-Cdc24-signaling pathway appears to control many aspects of yeast-cell polarization and budding. Ras proteins control the activity of Cdc24, a guanine -nucleotide exchange factor, which, in turn, controls the activation of downstream effector proteins, such as Cdc42 (Zhao et al 1995;Bassilana et al 2003). In C. neoformans, mutation of either the RAS1 or CDC24 gene results in a mutant strain that cannot efficiently repolarize its actin cytoskeleton after exposure to stresses, such as elevated temperatures (37˚C).…”