白念珠菌转录因子Cas5通过调控Crz1激活钙信号通路的分子机制研究

钙信号通路是白念珠菌应答环境压力的重要信号途径。虽然Crz1对于真菌胞内钙稳态系统的精细调节至关重要，但基因敲除Crz1并未改变白念珠菌毒力及其药物敏感性，提示钙信号通路参与这两方面的调控尚存其他未知因子。课题组前期工作首次发现转录因子Cas5参与白念珠菌钙信号通路调控，并与该菌毒力和药物敏感性直接相关。此外，敲除Cas5后，Crz1蛋白表达水平显著下降，且在钙离子诱导下Crz1无法进入细胞核发挥功能，表明Cas5可能通过调控Crz1激活钙信号通路。本项目拟通过遗传学、功能基因组学及分子生物学技术等展开研究：1）揭示Cas5如何与Crz1等已知因子相互作用共同调控白念珠菌钙信号通路的激活；2）阐明Cas5介导的钙信号通路如何调控白念珠菌毒力与药物敏感性。该研究对全面解析白念珠菌钙信号调控通路和基于该通路探索新型抗真菌药物靶点具有重要意义。

Candida albicans is able to respond to multiple environmental pressures through a very important calcium signaling pathway. Previous reports have assigned a key role to the transcription factor Crz1 in intracellular calcium homeostasis. However, Crz1 is dispensable for pathogenicity and drug sensitivity of Candida albicans, implying that the calcium signaling pathway requires other unknown factors in regulating fungal virulence and drug sensitivity. By screening our homozygous gene deletion library, we identified a novel factor Cas5 operating in calcium signaling pathway. And this transcription factor is involved in regulation of virulence and drug sensitivity of Candida albicans. In addition, after knockout of Cas5, the expression level of Crz1 protein was significantly decreased, and Crz1 could not enter the nucleus to function under the induction of calcium, which means that Cas5 activates calcium signaling pathway through regulating Crz1. This project is intended to be studied by genetics, functional genomics and molecular biology with two specific aims: 1) Mechanisms of how Cas5 regulates the activation of calcium signaling pathway by interacting with other known factors such as Crz1; 2) Mechanisms of how Cas5-mediated calcium signaling pathway regulates the virulence and drug sensitivity. This study is expected to gain a more comprehensive picture of calcium signaling pathway and we hope that our proposed research can discover new targets of anti-fungal drugs.