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Novel molecular mechanisms of iron sensing and homeostasis in filamentous fungi

丝状真菌铁感应和稳态的新分子机制

基本信息

批准号：
241377596
负责人：
Professor Dr. Axel Brakhage, Ph.D.
金额：
--
依托单位：
Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. Hans-Knöll-Institut
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/241377596?language=en
关键词：
Novel molecular mechanisms iron sensing

项目摘要

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.

铁是许多细胞过程所必需的，但过量有毒。此外，对铁饥饿的适应是包括真菌在内的病原体的关键毒力决定因素。由于宿主和病原体维持铁稳态的机制存在根本差异，铁代谢是提高抗真菌治疗和诊断真菌感染的一个有吸引力的新靶点。在包括最常见的气载真菌病原体烟曲霉（Aspergillus fumigatus）在内的多种真菌中，铁调节因子HapX通过与CCAAT结合复合物（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在铁抗性中也是必不可少的，这表明HapX可以感知细胞内的铁状态来协调转录反应，遗传学家、生物化学家和结构生物学家计划合作研究HapX/CBC复合物作为铁传感器、转录抑制因子和激活因子以及启动子组织者的功能。在体内和体外分析相结合的结构检查所涉及的蛋白质/蛋白质和蛋白质/DNA复合物，以阐明这些新的调节机制，在真核生物。