Deciphering iron homeostasis using the fission yeast model

标题.使用裂变酵母模型破译铁稳态。每个真核细胞都致力于获得铁（Fe）。由于其失去和获得一个电子的特性，Fe在与DNA复制，呼吸和能量产生等重要过程相关的几种蛋白质的活性中心是必需的。尽管铁在自然界中含量丰富，但通常以生物学上不可用的形式存在。因此，细胞发展了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铁收购血红素。虽然已知是铁的重要来源，但从该来源获得铁所需的细胞组分仍然知之甚少。粟酒裂殖酵母是一个优秀的模型系统，了解真核细胞生长，代谢和营养物质的获取的许多方面。研究S。粟酒裂殖酵母已经鉴定了许多在铁稳态调节中起作用的新基因，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的事实相一致，血红素转运/伴侣蛋白的发现已经出现，但对它们知之甚少，包括它们的作用机制以及它们如何被调节。在这项资助申请中，我们建议研究铁代谢蛋白的新功能，包括一些似乎参与从血红素中获取铁的蛋白。在未来5年内，我们将把研究计划集中在以下具体目标上。1.研究Shu 1的作用和作用机制，Shu 1是血红素获取所需的一种新型细胞表面蛋白。2.表征Shu 1响应于高水平血红素而内化的内吞途径。3.阐明Abc 3在液泡血红素或铁库运输中的分子参与。此外，还将研究与Shu 1或其血红素获取途径相关的其他蛋白质，包括Str 3（一种未表征的Fe调节跨膜蛋白）和Frp 2（一种推定的铁还原酶）。该建议的独创性依赖于研究一种新的且特征不明显的血红素/Fe获取途径，该途径最终可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才的特殊机会，使这些科学家对加拿大生物技术部门和/或学术研究界非常有价值。

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.**