Mating-Type-Specific and Nonspecific PAK Kinases Play Shared and Divergent Roles in Cryptococcus neoformans

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Abstract
Cryptococcus neoformans is an opportunistic fungal pathogen with a defined sexual cycle involving fusion of haploid MAT α and MAT a cells. Virulence has been linked to the mating type, and MAT α cells are more virulent than congenic MAT a cells. To study the link between the mating type and virulence, we functionally analyzed three genes encoding homologs of the p21-activated protein kinase family: STE20 α, STE20 a, and PAK1 . In contrast to the STE20 genes that were previously shown to be in the mating-type locus, the PAK1 gene is unlinked to the mating type. The STE20 α, STE20 a, and PAK1 genes were disrupted in serotype A and D strains of C. neoformans , revealing central but distinct roles in mating, differentiation, cytokinesis, and virulence. ste20 α pak1 and ste20 a pak1 double mutants were synthetically lethal, indicating that these related kinases share an essential function. In summary, our studies identify an association between the STE20 α gene, the MAT α locus, and virulence in a serotype A clinical isolate and provide evidence that PAK kinases function in a MAP kinase signaling cascade controlling the mating, differentiation, and virulence of this fungal pathogen.