Iron is an essential nutrient for almost every organism. It is required by every cell in the human body, yet it can also be a potent cellular toxin. Iron is essential because enzymes that require iron cofactors (namely, heme, iron-sulfur clusters, mononuclear, and diiron centers) are involved in virtually every major metabolic process in the cell. Iron deficiency continues to be the most common nutritional deficiency in the world, especially among children and women of childbearing age, where it causes anemia and impairs neurological development and function. Although the pathogenesis of anemia in iron deficiency is well understood, other manifestations of iron deficiency are not understood at the cellular or metabolic levels. Iron overload is a feature of an increasing number of human diseases, including genetic disorders such as hereditary hemochromatosis, thalassemias, and Friedreich’s ataxia, as well as chronic inflammatory diseases of the liver, such as hepatitis C. Our laboratory focuses on the genetics and cell biology of iron uptake and utilization in eukaryotes. Previously, we identified and characterized systems of iron transport in baker’s yeast, Saccharomyces cerevisiae. More recently, we have used the genetic tractability of yeast to focus on the intracellular trafficking and distribution of iron cofactors in yeast and mammalian cells.
Mammalian cells express hundreds of metalloproteins. Most contain the abundant metals iron and zinc, while others contain various trace metals such as copper, manganese, molybdenum, and cobalt. Although incorporation of the appropriate metal ion(s) into cellular metalloproteins is a critical and essential process, the mechanism by which most metalloproteins receive their specific cofactor is unknown. Some proteins rely on metallochaperones—proteins that specifically bind metal ions and deliver them to target enzymes and transporters through direct protein-protein interactions.
We identified poly (rC) binding protein 1 (PCBP1) as a cytosolic iron chaperone that delivers iron to ferritin. In mammals, ferritin is an iron storage protein consisting of 24 subunits of heavy (H) and light (L) peptides that assemble into a hollow sphere into which iron is deposited. PCBP1 binds both Fe(II) and ferritin and facilitates the incorporation of iron into ferritin. Non-heme iron enzymes in the cytosol require PCBP1 for the insertion of iron cofactors. We have identified additional components of the intracellular iron trafficking system. Murine models of conditional PCBP1 deficiency reveal the critical roles of PCBPs in cells and tissues.
Our research program couples the power of yeast genetics, mammalian cell biology, and murine models to understand the the cell biology and biochemistry of iron chaperones in mammalian iron utilization in human health and disease.
Need for Further Study
We identified poly (rC) binding protein 1 (PCBP1) as a cytosolic iron chaperone that delivers iron to ferritin. In mammals, ferritin is an iron storage protein consisting of 24 subunits of heavy (H) and light (L) peptides that assemble into a hollow sphere into which iron is deposited. PCBP1 binds both Fe(II) and ferritin and facilitates the incorporation of iron into ferritin. Studies are underway to identify other iron enzymes that require PCBP1 for the insertion of iron cofactors and to further characterize the cell biology and biochemistry of iron chaperones in mammals.
- Chief, Genetics and Metabolism Section, LDB, NIDDK, NIH, 2005 - present
- Member of the Association of American Physicians (AAP) 2019
- Fellow of American Association for the Advancement of Science (AAAS) 2011
- American Society for Clinical Investigation (ASCI) 2004
- Tenure-track Investigator, Liver Diseases Section, NIDDK, NIH, 1998 - 2004
- Clinical Associate in Genetics NICHD, NIH, 1995 – 1998
- Postdoctoral Fellow NICHD, NIH, 1990 – 1995
- Resident in Internal Medicine Johns Hopkins Hospital, 1987 – 1990
- M.D. Duke University, 1987
- B.A. Duke University, 1983
- Patel SJ, Protchenko O, Shakoury-Elizeh M, Baratz E, Jadhav S, Philpott CC. The iron chaperone and nucleic acid-binding activities of poly(rC)-binding protein 1 are separable and independently essential. Proc Natl Acad Sci U S A. 2021;118(25).
- Protchenko O, Baratz E, Jadhav S, Li F, Shakoury-Elizeh M, Gavrilova O, Ghosh MC, Cox JE, Maschek JA, Tyurin VA, Tyurina YY, Bayir H, Aron AT, Chang CJ, Kagan VE, Philpott CC. Iron Chaperone Poly rC Binding Protein 1 Protects Mouse Liver From Lipid Peroxidation and Steatosis. Hepatology. 2021;73(3):1176-1193.
- Patel SJ, Frey AG, Palenchar DJ, Achar S, Bullough KZ, Vashisht A, Wohlschlegel JA, Philpott CC. A PCBP1-BolA2 chaperone complex delivers iron for cytosolic [2Fe-2S] cluster assembly. Nat Chem Biol. 2019;15(9):872-881.
- Ryu MS, Zhang D, Protchenko O, Shakoury-Elizeh M, Philpott CC. PCBP1 and NCOA4 regulate erythroid iron storage and heme biosynthesis. J Clin Invest. 2017;127(5):1786-1797.
- Frey AG, Nandal A, Park JH, Smith PM, Yabe T, Ryu MS, Ghosh MC, Lee J, Rouault TA, Park MH, Philpott CC. Iron chaperones PCBP1 and PCBP2 mediate the metallation of the dinuclear iron enzyme deoxyhypusine hydroxylase. Proc Natl Acad Sci U S A. 2014;111(22):8031-6.
Related Scientific Focus Areas
Genetics and Genomics
Molecular Biology and Biochemistry
This page was last updated on Thursday, November 30, 2023