Caroline C. Philpott, M.D.

Senior Investigator

Genetics and Metabolism Section, Liver Diseases Branch

NIDDK

Building 10, Room 9B16A
10 Center Drive
Bethesda, MD 20814

301-435-4018

carolinep@intra.niddk.nih.gov

Research Topics

Current Research

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. 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.

The final step of heme biosynthesis occurs within the mitochondria, yet heme proteins are located in virtually every compartment of the cell. Thus heme, a hydrophobic molecule, must be transferred to the cytosol and to other membrane-bound organelles for insertion into newly synthesized heme proteins. Soluble heme-binding proteins have been identified in plants and mammals, but their roles in cellular heme metabolism or transport are unclear. We are conducting studies to identify and characterize the proteins involved in intracellular heme trafficking.

Our research program couples the power of yeast genetics, mammalian cell biology, and murine models to understand the biology of 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.

Soluble heme-binding proteins have been identified in plants and mammals, but their roles in cellular heme metabolism or transport are unclear. We are conducting studies to identify and characterize the proteins involved in intracellular heme trafficking.

Biography

  • 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

Selected Publications

  1. Frey AG, Palenchar DJ, Wildemann JD, Philpott CC. A Glutaredoxin-BolA Complex Serves as an Iron-Sulfur Cluster Chaperone for the Cytosolic Cluster Assembly Machinery. J Biol Chem. 2016.

  2. 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.

  3. 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.

  4. Nandal A, Ruiz JC, Subramanian P, Ghimire-Rijal S, Sinnamon RA, Stemmler TL, Bruick RK, Philpott CC. Activation of the HIF prolyl hydroxylase by the iron chaperones PCBP1 and PCBP2. Cell Metab. 2011;14(5):647-57.

  5. Shi H, Bencze KZ, Stemmler TL, Philpott CC. A cytosolic iron chaperone that delivers iron to ferritin. Science. 2008;320(5880):1207-10.


This page was last updated on August 31st, 2016