Deciphering iron homeostasis using the fission yeast model

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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.**