title: Mating-type-specific and nonspecific PAK kinases play shared and divergent roles in Cryptococcus neoformans.
abstract: Cryptococcus neoformans is an opportunistic fungal pathogen with a defined sexual cycle involving fusion of haploid MATalpha and MATa cells. Virulence has been linked to the mating type, and MATalpha cells are more virulent than congenic MATa 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: STE20alpha, STE20a, 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 STE20alpha, STE20a, 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. ste20alpha pak1 and ste20a pak1 double mutants were synthetically lethal, indicating that these related kinases share an essential function. In summary, our studies identify an association between the STE20alpha gene, the MATalpha 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.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Connie B
authors.initials: CB
authors.lastname: Nichols
authors.forename: Klaus B
authors.initials: KB
authors.lastname: Lengeler
authors.forename: Maria E
authors.initials: ME
authors.lastname: Cardenas
authors.forename: Gary M
authors.initials: GM
authors.lastname: Cox
authors.forename: John R
authors.initials: JR
authors.lastname: Perfect
authors.forename: Joseph
authors.initials: J
authors.lastname: Heitman
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division; D003453:Cryptococcosis / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity; D005260:Female; D005656:Fungal Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism; D006238:Haploidy; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011817:Rabbits; D011995:Recombination, Genetic; D012098:Reproduction; D016415:Sequence Alignment; D012703:Serotyping; D013696:Temperature; D014157:Transcription Factors / Q000145:classification / Q000235:genetics / Q000378:metabolism; D014774:Virulence / Q000502:physiology
chemical_list: D005656:Fungal Proteins; D014157:Transcription Factors; D011494:Protein Kinases; C036447:protease activated kinase I; D017346:Protein Serine-Threonine Kinases