Wang Ping, Nichols Connie B, Lengeler Klaus B, Cardenas Maria E, Cox Gary M, Perfect John R, Heitman Joseph
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Eukaryot Cell. 2002 Apr;1(2):257-72. doi: 10.1128/EC.1.2.257-272.2002.
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.
新型隐球菌是一种机会性真菌病原体，具有明确的有性生殖周期，涉及单倍体MATα和MATa细胞的融合。毒力与交配型有关，MATα细胞比同基因的MATa细胞毒力更强。为了研究交配型与毒力之间的联系，我们对编码p21激活蛋白激酶家族同源物的三个基因进行了功能分析：STE20α、STE20a和PAK1。与先前显示位于交配型位点的STE20基因不同，PAK1基因与交配型无关。STE20α、STE20a和PAK1基因在新型隐球菌的A血清型和D血清型菌株中被破坏，揭示了它们在交配、分化、胞质分裂和毒力中核心但不同的作用。ste20α pak1和ste20a pak1双突变体具有合成致死性，表明这些相关激酶具有共同的基本功能。总之，我们的研究确定了STE20α基因、MATα位点与A血清型临床分离株毒力之间的关联，并提供了证据表明PAK激酶在控制这种真菌病原体交配、分化和毒力的丝裂原活化蛋白激酶信号级联中发挥作用。
