Li Lie, Shen Gui, Zhang Zheng-Guang, Wang Yan-Li, Thompson Jill K, Wang Ping
Department of Pediatrics,The Research Institute for Children, Louisiana State University Health Sciences Center, New Orleans, LA 70118, USA.
Mol Biol Cell. 2007 Nov;18(11):4201-9. doi: 10.1091/mbc.e07-02-0136. Epub 2007 Aug 15.
Perturbation of pheromone signaling modulates not only mating but also virulence in Cryptococcus neoformans, an opportunistic human pathogen known to encode three Galpha, one Gbeta, and two Ggamma subunit proteins. We have found that Galphas Gpa2 and Gpa3 exhibit shared and distinct roles in regulating pheromone responses and mating. Gpa2 interacted with the pheromone receptor homolog Ste3alpha, Gbeta subunit Gpb1, and RGS protein Crg1. Crg1 also exhibited in vitro GAP activity toward Gpa2. These findings suggest that Gpa2 regulates mating through a conserved signaling mechanism. Moreover, we found that Ggammas Gpg1 and Gpg2 both regulate pheromone responses and mating. gpg1 mutants were attenuated in mating, and gpg2 mutants were sterile. Finally, although gpa2, gpa3, gpg1, gpg2, and gpg1 gpg2 mutants were fully virulent, gpa2 gpa3 mutants were attenuated for virulence in a murine model. Our study reveals a conserved but distinct signaling mechanism by two Galpha, one Gbeta, and two Ggamma proteins for pheromone responses, mating, and virulence in Cryptococcus neoformans, and it also reiterates that the link between mating and virulence is not due to mating per se but rather to certain mating-pathway components that encode additional functions promoting virulence.
信息素信号的扰动不仅调节新型隐球菌（一种已知编码三种Gα、一种Gβ和两种Gγ亚基蛋白的机会性人类病原体）的交配，还调节其毒力。我们发现Gα亚基Gpa2和Gpa3在调节信息素反应和交配中表现出共同和不同的作用。Gpa2与信息素受体同源物Ste3α、Gβ亚基Gpb1和RGS蛋白Crg1相互作用。Crg1在体外也对Gpa2表现出GAP活性。这些发现表明Gpa2通过保守的信号机制调节交配。此外，我们发现Gγ亚基Gpg1和Gpg2都调节信息素反应和交配。gpg1突变体在交配中减弱，而gpg2突变体不育。最后，尽管gpa2、gpa3、gpg1、gpg2和gpg1 gpg2突变体具有完全的毒力，但gpa2 gpa3突变体在小鼠模型中的毒力减弱。我们的研究揭示了新型隐球菌中两种Gα、一种Gβ和两种Gγ蛋白在信息素反应、交配和毒力方面保守但不同的信号机制，并且还重申交配和毒力之间的联系不是由于交配本身，而是由于某些编码促进毒力的额外功能的交配途径成分。
