Hicks Julie K, D'Souza Cletus A, Cox Gary M, Heitman Joseph
Department of Molecular Genetics and Microbiology, Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710, USA.
Eukaryot Cell. 2004 Feb;3(1):14-26. doi: 10.1128/EC.3.1.14-26.2004.
Our earlier findings established that cyclic AMP-dependent protein kinase functions in a signaling cascade that regulates mating and virulence of Cryptococcus neoformans var. grubii (serotype A). Mutants lacking the serotype A protein kinase A (PKA) catalytic subunit Pka1 are unable to mate, fail to produce melanin or capsule, and are avirulent in animal models, whereas mutants lacking the PKA regulatory subunit Pkr1 overproduce capsule and are hypervirulent. Because other mutations have been observed to confer different phenotypes in two diverged varieties of C. neoformans (grubii variety [serotype A] and neoformans variety [serotype D]), we analyzed the functions of the PKA genes in the serotype D neoformans variety. Surprisingly, the Pka1 catalytic subunit was not required for mating, haploid fruiting, or melanin or capsule production of serotype D strains. Here we identify a second PKA catalytic subunit gene, PKA2, that is present in both serotype A and D strains of C. neoformans. The divergent Pka2 catalytic subunit was found to regulate mating, haploid fruiting, and virulence factor production in serotype D strains. In contrast, Pka2 has no role in mating, melanin production, or capsule formation in serotype A strains. Our studies illustrate how different components of signaling pathways can be co-opted and functionally specialized during the evolution of related but distinct varieties or subspecies of a human fungal pathogen.
我们早期的研究结果表明，环磷酸腺苷依赖性蛋白激酶在一个信号级联反应中发挥作用，该信号级联反应调节新型隐球菌格鲁比变种（血清型A）的交配和毒力。缺乏血清型A蛋白激酶A（PKA）催化亚基Pka1的突变体无法交配，不能产生黑色素或荚膜，并且在动物模型中无致病性；而缺乏PKA调节亚基Pkr1的突变体则过度产生荚膜且具有高致病性。由于已观察到其他突变在新型隐球菌的两个不同变种（格鲁比变种[血清型A]和新生变种[血清型D]）中赋予不同的表型，我们分析了血清型D新生变种中PKA基因的功能。令人惊讶的是，血清型D菌株的交配、单倍体产孢或黑色素或荚膜产生并不需要Pka1催化亚基。在此，我们鉴定出第二个PKA催化亚基基因PKA2，它存在于新型隐球菌的血清型A和D菌株中。发现不同的Pka2催化亚基可调节血清型D菌株的交配、单倍体产孢和毒力因子产生。相比之下，Pka2在血清型A菌株的交配、黑色素产生或荚膜形成中没有作用。我们的研究说明了在一种人类真菌病原体的相关但不同的变种或亚种的进化过程中，信号通路的不同组分是如何被选用并在功能上特化的。
