Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Fungal Genet Biol. 2013 Aug;57:58-75. doi: 10.1016/j.fgb.2013.05.006. Epub 2013 Jun 5.
A genome wide analysis of the human fungal pathogen Cryptococcus neoformans var. grubii has revealed a number of duplications of highly conserved genes involved in morphogenesis. Previously, we reported that duplicate Cdc42 paralogs provide C. neoformans with niche-specific responses to environmental stresses: Cdc42 is required for thermotolerance, while Cdc420 supports the formation of titan cells. The related Rho-GTPase Rac1 has been shown in C. neoformans var. neoformans to play a major role in filamentation and to share Cdc42/Cdc420 binding partners. Here we report the characterization of a second Rac paralog in C. neoformans, Rac2, and describe its overlapping function with the previously described CnRac, Rac1. Further, we demonstrate that the Rac paralogs play a primary role in polarized growth via the organization of reactive oxygen species and play only a minor role in the organization of actin. Finally, we provide preliminary evidence that pharmacological inhibitors of Rac activity and actin stability have synergistic activity.
对人类真菌病原体新型隐球菌 var. grubii 的全基因组分析揭示了许多参与形态发生的高度保守基因的重复。之前，我们报道了重复的 Cdc42 同源物为新型隐球菌提供了对环境压力的特定小生境反应：Cdc42 是耐热所必需的，而 Cdc420 则支持泰坦细胞的形成。在新型隐球菌 var. neoformans 中，相关的 Rho-GTPase Rac1 已被证明在菌丝形成中起主要作用，并与 Cdc42/Cdc420 结合伙伴共享。在这里，我们报告了新型隐球菌中第二个 Rac 同源物 Rac2 的特征，并描述了其与先前描述的 CnRac、Rac1 的重叠功能。此外，我们证明 Rac 同源物通过活性氧的组织在极化生长中起主要作用，而在肌动蛋白的组织中仅起次要作用。最后，我们提供了初步证据表明 Rac 活性和肌动蛋白稳定性的药理学抑制剂具有协同作用。
