Integration of the tricarboxylic acid (TCA) cycle with cAMP signaling and Sfl2 pathways in the regulation of CO2 sensing and hyphal development in Candida albicans.
Integration of the tricarboxylic acid (TCA) cycle with cAMP signaling and Sfl2 pathways in the regulation of CO2 sensing and hyphal development in Candida albicans.
复制标题
三羧酸 (TCA) 循环与 cAMP 信号传导和 Sfl2 通路在白色念珠菌 CO2 传感和菌丝发育调节中的整合
DOI：
10.1371/journal.pgen.1006949
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发表时间：
2017-08
期刊：
影响因子：
4.5
通讯作者：
Huang G
中科院分区：
文献类型：
--
作者：
Tao L;Zhang Y;Fan S;Nobile CJ;Guan G;Huang G
形态转变和代谢调节是人类真菌病原体白色念珠菌适应宿主环境变化的关键。在这项研究中，我们建立了一个三羧酸（TCA）循环中的中心代谢途径突变体库，并研究了这些基因缺失对C。白色念珠菌生物学TCA循环的失活削弱了C.白色念珠菌利用不可发酵的碳源，并在几种培养条件下显著减弱细胞生长速率。通过整合Ras 1-cAMP信号通路和热休克因子型转录调节因子Sfl 2，我们发现TCA循环在CO2传感和菌丝发育的调节中起着重要作用。TCA循环和cAMP信号通路通过分子连接物ATP和CO2协调调节菌丝生长。TCA循环的失活导致细胞内ATP和cAMP水平降低，从而影响Ras 1调节的cAMP信号通路的激活。反过来，Ras 1-cAMP信号通路通过Efg 1和Sfl 2介导的转录调节来控制TCA循环，以响应升高的CO2水平。蛋白激酶A（PKA）催化亚基Tpk 1，但不是Tpk 2，可能在这种调节中发挥重要作用。在高CO2条件下，Sfl 2特异性结合几种TCA循环和菌丝相关基因。全球转录分析实验表明，Sfl 2确实是需要的基因表达变化发生在这些升高的CO2水平。我们的研究揭示了TCA循环在CO2传感和菌丝发育中的调节作用，并建立了TCA循环和Ras 1-cAMP信号通路之间的新联系。通过TCA循环的能量代谢和线粒体电子传递是人类真菌病原体白色念珠菌在宿主中生存和繁殖的关键。这在一定程度上是由于C。白色念珠菌是克拉布特里阴性菌种，因此只有在有氧气时才进行呼吸。在这里，我们调查的作用，TCA循环在菌丝发育和CO2传感器在C。白色念珠菌通过使用ATP和细胞信号分子CO2，TCA循环与Ras 1-cAMP信号通路整合，Ras 1-cAMP信号通路是菌丝生长的中心调节因子，以控制基本的细胞生物学过程。热休克因子型转录调节因子Sfl 2与cAMP信号通路的下游转录因子Efg 1共同调控CO2诱导的菌丝生长。白色念珠菌。SFL 2的缺失导致在升高的CO2水平下的全局转录响应的丧失。我们的研究表明，TCA循环不仅在细胞代谢中占据中心地位，而且还通过与Ras 1-cAMP信号通路的整合来调节其他生物学过程，如CO2感应和菌丝发育。白色念珠菌
Morphological transitions and metabolic regulation are critical for the human fungal pathogen Candida albicans to adapt to the changing host environment. In this study, we generated a library of central metabolic pathway mutants in the tricarboxylic acid (TCA) cycle, and investigated the functional consequences of these gene deletions on C. albicans biology. Inactivation of the TCA cycle impairs the ability of C. albicans to utilize non-fermentable carbon sources and dramatically attenuates cell growth rates under several culture conditions. By integrating the Ras1-cAMP signaling pathway and the heat shock factor-type transcription regulator Sfl2, we found that the TCA cycle plays fundamental roles in the regulation of CO2 sensing and hyphal development. The TCA cycle and cAMP signaling pathways coordinately regulate hyphal growth through the molecular linkers ATP and CO2. Inactivation of the TCA cycle leads to lowered intracellular ATP and cAMP levels and thus affects the activation of the Ras1-regulated cAMP signaling pathway. In turn, the Ras1-cAMP signaling pathway controls the TCA cycle through both Efg1- and Sfl2-mediated transcriptional regulation in response to elevated CO2 levels. The protein kinase A (PKA) catalytic subunit Tpk1, but not Tpk2, may play a major role in this regulation. Sfl2 specifically binds to several TCA cycle and hypha-associated genes under high CO2 conditions. Global transcriptional profiling experiments indicate that Sfl2 is indeed required for the gene expression changes occurring in response to these elevated CO2 levels. Our study reveals the regulatory role of the TCA cycle in CO2 sensing and hyphal development and establishes a novel link between the TCA cycle and Ras1-cAMP signaling pathways. Energy metabolism through the TCA cycle and mitochondrial electron transport are critical for the human fungal pathogen Candida albicans to survive and propagate in the host. This is, in part, due to the fact that C. albicans is a Crabtree-negative species, and thus exclusively uses respiration when oxygen is available. Here, we investigate the roles of the TCA cycle in hyphal development and CO2 sensing in C. albicans. Through the use of ATP and the cellular signaling molecule CO2, the TCA cycle integrates with the Ras1-cAMP signaling pathway, which is a central regulator of hyphal growth, to govern basic cellular biological processes. Together with Efg1, a downstream transcription factor of the cAMP signaling pathway, the heat shock factor-type transcription regulator Sfl2 controls CO2-induced hyphal growth in C. albicans. Deletion of SFL2 results in the loss of global transcriptional responses under elevated CO2 levels. Our study indicates that the TCA cycle not only occupies the central position of cellular metabolism but also regulates other biological processes such as CO2 sensing and hyphal development through integration with the Ras1-cAMP signaling pathway in C. albicans.