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Eukaryotic Cell, June 2005, p. 1066-1078, Vol. 4, No. 6
1535-9778/05/$08.00+0     doi:10.1128/EC.4.6.1066-1078.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

A Rac Homolog Functions Downstream of Ras1 To Control Hyphal Differentiation and High-Temperature Growth in the Pathogenic Fungus Cryptococcus neoformans

Marcelo A. Vallim,{dagger} Connie B. Nichols,{dagger} Larissa Fernandes, Kari L. Cramer, and J. Andrew Alspaugh*

Departments of Medicine and Molecular Genetics/Microbiology, Duke University Medical Center, Durham, North Carolina

Received 2 March 2005/ Accepted 29 March 2005

The Cryptococcus neoformans Ras1 protein serves as a central regulator for several signaling pathways. Ras1 controls the induction of the mating pheromone response cascade as well as a distinct signaling pathway that allows this pathogenic fungus to grow at human physiological temperature. To characterize elements of the Ras1-dependent high-temperature growth pathway, we performed a multicopy suppressor screen, identifying genes whose overexpression allows the ras1 mutant to grow at 37°C. Using this genetic technique, we identified a C. neoformans gene encoding a Rac homolog that suppresses multiple ras1 mutant phenotypes. Deletion of the RAC1 gene does not affect high-temperature growth. However, a rac1 mutant strain demonstrates a profound defect in haploid filamentation as well as attenuated mating. In a yeast two-hybrid assay, Rac1 physically interacts with the PAK kinase Ste20, which similarly regulates hyphal formation in this fungus. Similar to Rac1, overexpression of the STE20{alpha} gene also restores high-temperature growth to the ras1 mutant. These results support a model in which the small G protein Rac1 acts downstream of Ras proteins and coordinately with Ste20 to control high-temperature growth and cellular differentiation in this human fungal pathogen.

* Corresponding author. Mailing address: DUMC 3355, Durham, NC 27710. Phone: (919) 684-0045. Fax: (919) 684-8902. E-mail: andrew.alspaugh{at}duke.edu.

{dagger} These authors contributed equally to the manuscript.

Eukaryotic Cell, June 2005, p. 1066-1078, Vol. 4, No. 6
1535-9778/05/$08.00+0     doi:10.1128/EC.4.6.1066-1078.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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