Deciphering iron homeostasis using the fission yeast model

使用裂殖酵母模型解读铁稳态

• 批准号: RGPIN-2015-04878
• 负责人: Labbé, Simon
• 金额: $ 3.28万
• 依托单位: Université de Sherbrooke
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=656243
• 关键词: Deciphering; iron; homeostasis; using; fission

Title. Deciphering iron homeostasis using the fission yeast model.***Each eukaryotic cell is committed to acquire iron (Fe). Because of its property to lose and gain one electron, Fe is required at the active center of several proteins that are associated with important processes such as DNA replication, respiration, and energy production. Although abundant in nature, iron is generally found in forms that are biologically unavailable. Cells have therefore developed different mechanisms to acquire it from the environment. In fungi, one of these mechanisms implies Fe acquisition from heme. Although known to be an important source of Fe, cellular components that are required for Fe acquisition from this source remain poorly understood. The yeast Schizosaccharomyces pombe is an outstanding model system for understanding many aspects of eukaryotic cell growth, metabolism, and nutrient acquisition. Studies of S. pombe have identified a number of novel genes that function in the regulation of iron homeostasis and have highlighted their existence and importance in other organisms. Consistent with the fact that free heme is hydrophobic and cytotoxic, the discovery of heme transport/chaperone proteins has emerged, yet little is known about them, including their mechanism of action and how they are regulated. In this grant application we propose to study new functions of iron metabolism proteins, including some that appear to be involved in iron acquisition from heme. During the next 5 years, we will focus our research program on the following specific aims. 1. Investigate the role and mechanism of action of Shu1, a novel cell surface protein that is required for heme acquisition. 2. Characterize the endocytic pathway by which Shu1 is internalized in response to high levels of heme. 3. Elucidate the molecular participation of Abc3 in the transport of vacuolar heme or Fe stores. Furthermore, additional proteins associated with Shu1 or its heme acquisition pathway will be also investigated, including Str3 (an uncharacterized Fe-regulated transmembrane protein) and Frp2 (a putative ferrireductase). The originality of this proposal relies on studying a novel and poorly characterized heme/Fe acquisition pathway that eventually could be used as a target for antifungal therapy. The proposed work will also allow the exceptional opportunity to train highly qualified personnel, making these scientists highly valuable to the Canadian biotech sector and/or academic research community.**

标题。使用分裂酵母模型破译铁的动态平衡。*每个真核细胞都致力于获得铁(Fe)。由于铁的性质是失去和获得一个电子，所以铁在几种蛋白质的活性中心是必需的，这些蛋白质与DNA复制、呼吸和能量产生等重要过程有关。虽然铁在自然界中含量丰富，但通常以生物形式无法获得的形式存在。因此，细胞已经发展出不同的机制来从环境中获得它。在真菌中，这些机制之一意味着从血红素中获得铁。虽然已知是铁的一个重要来源，但从这个来源获取铁所需的细胞成分仍然知之甚少。酵母裂殖酵母是了解真核细胞生长、新陈代谢和营养获取的许多方面的优秀模型系统。对S.pombe的研究已经发现了一些新的基因，它们在铁稳态的调节中发挥作用，并强调了它们在其他生物体中的存在和重要性。与游离血红素具有疏水性和细胞毒性这一事实相一致的是，发现了血红素转运/伴侣蛋白，但人们对它们知之甚少，包括它们的作用机制和它们是如何调节的。在这项拨款申请中，我们建议研究铁代谢蛋白的新功能，包括一些似乎与从血红素中获取铁有关的功能。在接下来的5年里，我们的研究计划将重点放在以下具体目标上。1.研究了一种新的细胞表面蛋白Shu1的作用及其机制。2.确定Shu1内化的内化途径，以响应高水平的血红素。3.阐明ABC3在空泡状血红素或铁库运输中的分子参与。此外，与Shu1或其血红素获取途径相关的其他蛋白质也将被研究，包括Str3(一种未鉴定的铁调节的跨膜蛋白)和Frp2(一种推定的铁还原酶)。这一建议的原创性依赖于研究一种新的、特征不佳的血红素/铁获取途径，该途径最终可能被用作抗真菌治疗的靶点。拟议的工作还将提供培训高素质人员的特殊机会，使这些科学家对加拿大生物技术部门和/或学术研究界具有极高的价值。**