NSF-BSF: Regulating iron homeostasis by controlling the fate of intracellular ferritin

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Iron is an essential micronutrient for virtually all living organisms and a crucial component of many biological processes. However, too much or too little iron can be problematic and a significant contributor to human diseases. Iron not immediately utilized by cells is stored in ferritin, a ubiquitous 24-subunit-nanostructure that plays a critical role in cellular and systemic iron homeostasis and serves as the principal reservoir of metabolic iron within the cell. The goals of this project are to understand the mechanisms of ferritin trafficking and regulation within and out of the cell and how these processes are controlled. This project will provide a strong interdisciplinary training experience for undergraduate and graduate students and for postdoctoral fellows at four different institutions in the US and Israel and thus extend unique opportunities for these trainees and their faculty mentors to work together and innovate. Iron homeostasis is a tightly regulated process through the tuning of cellular iron import, export, and storage. Different proteins and iron regulators including the peptide hormone hepcidin, the iron regulatory proteins IRP1 and IRP2, the hypoxia inducible factor (HIF), the iron chaperone protein PCBP1, the nuclear receptor coactivator NCOA4, and the iron storage protein ferritin play important roles in the regulation of iron homeostasis. Despite intense research over the past decades and the physiological significance of iron homeostasis, there is a lack of full understanding of the molecular mechanisms underlying both cellular and systemic iron homeostasis. Using a combination of structural and molecular biology, spectroscopy, fluorescence microscopy, quantitative proteomics, and analytical and biophysical tools, the team will address fundamental questions in iron metabolism and will delineate the mechanisms that determine the fate of cellular ferritin and its trafficking route, from the protein-protein molecular level to the cellular level. For the first time, the investigators will explore biochemical, biophysical, structural, and cellular elucidation of previously uncharacterized NCOA4/PCBP1/ferritin interactions. The background and interdisciplinary nature of the proposed research will create unique opportunities to promote STEM research and education for undergraduate and graduate students, particularly historically underrepresented and economically disadvantaged students. Additionally, all trainees and senior research personnel will be exposed to different technologies, scientific communities, and research opportunities with the goal of enhancing innovation, scientific training, and citizenship in an increasingly global society.This collaborative US/Israel project is supported by the US National Science Foundation and the Israeli Binational Science Foundation.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.