A PAS Protein Directs Metabolic Reprogramming during Cryptococcal Adaptation to Hypoxia.
A PAS Protein Directs Metabolic Reprogramming during Cryptococcal Adaptation to Hypoxia.
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作者：
Zhao Y;Lin X
新生芽孢杆菌是真菌性脑膜炎的主要病原体，约占所有艾滋病毒相关死亡病例的15%。虽然新生隐孢子菌是一种专性好氧真菌，但它很好地适应了真菌在宿主或环境中可能遇到的缺氧条件。对于好氧生物来说，低氧压(低氧)是一种生理挑战。为了应对这样的挑战，必须调整代谢途径，如用于能源生产的代谢途径。在高等真核生物中，许多这样的代谢变化是由保守的低氧诱导因子(HIF)调控的。然而，在真菌或原生生物中没有HIF同源物，对于在低等真核生物中指导低氧适应的导体也知之甚少。在这里，我们发现转录因子Pas2控制代谢基因的转录水平，从而在人类真菌病原体新生隐球菌中重新连接代谢以适应低氧适应。通过遗传学、蛋白质组学和生化分析，我们证明了Pas2与另一个转录因子RDS2在调节隐球菌的低氧适应中直接相互作用。PAS2/RDS2复合体是代谢灵活性的关键转录调节因子。它对新陈代谢的调节，在呼吸和发酵之间重新布线，对于我们理解隐球菌对低氧水平的反应至关重要。
C. neoformans is the main causative agent of fungal meningitis that is responsible for about 15% of all HIV-related deaths. Although an obligate aerobic fungus, C. neoformans is well adapted to hypoxia conditions that the fungus could encounter in the host or the environment. To aerobic organisms, low oxygen tension (hypoxia) presents a physiological challenge. To cope with such a challenge, metabolic pathways such as those used in energy production have to be adjusted. Many of such metabolic changes are orchestrated by the conserved hypoxia-inducible factors (HIFs) in higher eukaryotes. However, there are no HIF homologs in fungi or protists, and not much is known about conductors that direct hypoxic adaptation in lower eukaryotes. Here, we discovered that the transcription factor Pas2 controls the transcript levels of metabolic genes and consequently rewires metabolism for hypoxia adaptation in the human fungal pathogen Cryptococcus neoformans. Through genetic, proteomic, and biochemical analyses, we demonstrated that Pas2 directly interacts with another transcription factor, Rds2, in regulating cryptococcal hypoxic adaptation. The Pas2/Rds2 complex represents the key transcription regulator of metabolic flexibility. Its regulation of metabolism rewiring between respiration and fermentation is critical to our understanding of the cryptococcal response to low levels of oxygen.