Transcriptional regulation of carbohydrate metabolism in the human pathogen Candida albicans.
Transcriptional regulation of carbohydrate metabolism in the human pathogen Candida albicans.
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DOI：
10.1371/journal.ppat.1000612
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发表时间：
2009-10
期刊：
影响因子：
6.7
通讯作者：
Whiteway M
中科院分区：
文献类型：
--
作者：
Askew C;Sellam A;Epp E;Hogues H;Mullick A;Nantel A;Whiteway M
糖酵解是一种代谢途径，对于呼吸或发酵的碳同化至关重要，因此对于所有生物体的生长至关重要。因此，糖酵解转录调控对于病原体试图殖民不同生态位的代谢灵活性非常重要。我们研究了人类真菌病原体白色念珠菌中碳水化合物代谢的转录控制，并确定了两个因子 Tye7p 和 Gal4p 作为糖酵解的关键调节因子。当呼吸受到抑制或氧气有限时，gal4tye7白色念珠菌菌株在以葡萄糖、果糖或甘露糖作为碳源培养时表现出严重的生长缺陷。 gal4tye7 菌株在 Galleria 和小鼠模型中也表现出减弱的毒力，支持致病性和代谢之间的联系。染色质免疫沉淀结合微阵列分析 (ChIP-CHIP) 和转录分析表明，Tye7p 结合糖酵解基因的启动子序列，并在可发酵或不可发酵碳源上生长期间激活其表达。 Gal4p 还结合糖酵解启动子序列并激活基因，但程度低于 Tye7p。有趣的是，Gal4p 的结合和激活是碳源依赖性的，并且在含有可发酵糖的培养基上生长期间比在甘油上更强。此外，Tye7p 和 Gal4p 负责在低氧生长条件下完全诱导糖酵解基因。 Tye7p 和 Gal4p 还调节独特的碳水化合物代谢基因组； Tye7p 结合并激活参与海藻糖、糖原和甘油代谢的基因，而 Gal4p 调节丙酮酸脱氢酶复合物。这表明 Tye7p 代表白色念珠菌碳水化合物代谢的关键转录调节因子，而 Gal4p 提供碳源依赖性基因表达微调，同时调节呼吸和发酵途径之间的代谢通量。病原体必须能够吸收环境中的碳源，以产生足够的能量和代谢物来生存。由于糖酵解是一种中心代谢途径，因此这种代谢灵活性非常重要。人类真菌感染中最常见的分离病原体是白色念珠菌，其全身性疾病的进展依赖于糖酵解。我们研究了白色念珠菌中的糖酵解转录调控，并定义了该途径的两个关键调控因子：Tye7p 和 Gal4p。我们证明这些因素对于白色念珠菌的体外和体内发酵生长都很重要，并且还调节糖酵解的输入和输出通量。 gal4tye7 菌株在 Galleria 和两种小鼠模型中表现出毒力减弱，这可能是由于限氧环境中的严重生长缺陷所致。 Gal4p 和 Tye7p 代表参与生物体致病性的真菌特异性调节因子，可用于开发抗真菌治疗。我们的研究描述了一种与模型酵母酿酒酵母根本不同的真菌糖酵解转录回路，提供了进一步的证据，表明酿酒酵母中的转录网络不必普遍代表真菌界。
Glycolysis is a metabolic pathway that is central to the assimilation of carbon for either respiration or fermentation and therefore is critical for the growth of all organisms. Consequently, glycolytic transcriptional regulation is important for the metabolic flexibility of pathogens in their attempts to colonize diverse niches. We investigated the transcriptional control of carbohydrate metabolism in the human fungal pathogen Candida albicans and identified two factors, Tye7p and Gal4p, as key regulators of glycolysis. When respiration was inhibited or oxygen was limited, a gal4tye7 C. albicans strain showed a severe growth defect when cultured on glucose, fructose or mannose as carbon sources. The gal4tye7 strain displayed attenuated virulence in both Galleria and mouse models as well, supporting the connection between pathogenicity and metabolism. Chromatin immunoprecipitation coupled with microarray analysis (ChIP-CHIP) and transcription profiling revealed that Tye7p bound the promoter sequences of the glycolytic genes and activated their expression during growth on either fermentable or non-fermentable carbon sources. Gal4p also bound the glycolytic promoter sequences and activated the genes although to a lesser extent than Tye7p. Intriguingly, binding and activation by Gal4p was carbon source-dependent and much stronger during growth on media containing fermentable sugars than on glycerol. Furthermore, Tye7p and Gal4p were responsible for the complete induction of the glycolytic genes under hypoxic growth conditions. Tye7p and Gal4p also regulated unique sets of carbohydrate metabolic genes; Tye7p bound and activated genes involved in trehalose, glycogen, and glycerol metabolism, while Gal4p regulated the pyruvate dehydrogenase complex. This suggests that Tye7p represents the key transcriptional regulator of carbohydrate metabolism in C. albicans and Gal4p provides a carbon source-dependent fine-tuning of gene expression while regulating the metabolic flux between respiration and fermentation pathways. Pathogens must be able to assimilate the carbon sources in their environment to generate sufficient energy and metabolites to survive. Since glycolysis is a central metabolic pathway, it is important for this metabolic flexibility. The most commonly isolated agent in human fungal infections, Candida albicans, depends upon glycolysis for the progression of systemic disease. We investigated glycolytic transcriptional regulation in C. albicans and defined two key regulators of the pathway, Tye7p and Gal4p. We demonstrated that these factors are important for the fermentative growth of C. albicans both in vitro and in vivo and also regulate the input and output fluxes of glycolysis. The gal4tye7 strain showed attenuated virulence in a Galleria and two mouse models, potentially due to the severe growth defect in oxygen-limiting environments. Gal4p and Tye7p represent fungal specific regulators involved in the pathogenicity of the organism that may be exploited in the development of antifungal treatments. Our study describes a fungal glycolytic transcriptional circuit that is fundamentally different from that of the model yeast Saccharomyces cerevisiae, providing further evidence that the transcriptional networks in S. cerevisiae need not be generally representative of the fungal kingdom.
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