Novel molecular mechanisms of iron sensing and homeostasis in filamentous fungi

铁是许多细胞过程所必需的，但过量的铁是有毒的。此外，对铁饥饿的适应是包括真菌在内的病原体的一个关键毒力决定因素。由于宿主和病原体维持铁稳态的机制存在根本差异，铁代谢成为改善抗真菌治疗和真菌感染诊断的新靶点。然而，需要更好地了解真菌铁稳态的分子基础。在包括最常见的空气传播真菌烟曲霉菌在内的各种真菌中，关键的铁调节因子HapX通过与CCAAT结合复合体(CBC)的相互作用而被证明是适应铁饥饿所必需的。最近，我们发现HapX对铁的抗性是必不可少的，这突显了HapX感知细胞铁状态以协调转录反应。遗传学家、生物化学家和结构生物学家计划进行的合作研究旨在从分子水平深入探讨HapX/CBC复合体作为铁传感器、转录抑制和激活因子以及启动子组织者的功能。体内和体外的分析结合所涉及的蛋白质/蛋白质和蛋白质/DNA复合体的结构检查来阐明真核生物中这些新的调控机制。

Iron is essential for numerous cellular processes but toxic in excess. Moreover, adaptation to iron starvation is a crucial virulence determinant of pathogens including fungi. Due to the fundamental differences in the mechanism employed by host and pathogens to maintain iron homeostasis, iron metabolism is an attractive new target for improvement of antifungal therapy and diagnosis of fungal infections. However, a better understanding of the molecular basis of fungal iron homeostasis is required.In various fungi including the most common airborne fungal pathogen Aspergillus fumigatus, the key iron regulator HapX has been shown to be required for adaptation to iron starvation via its interaction with the CCAAT-binding complex (CBC). Recently, we found that HapX is in addition essential for iron resistance, which underlines that HapX senses the cellular iron status to coordinate the transcriptional response.The planned collaborative studies by geneticists, biochemists and structural biologists aim to explore in molecular depth the functions of the HapX/CBC complex as iron sensor, transcriptional repressor and activator, as well as promoter organizer. In vivo and in vitro analyses are combined with structural examinations of the involved protein/protein and protein/DNA complexes to elucidate these novel regulatory mechanisms in eukaryotes.