Research Associate Professor of Pathology
B.S. Brigham Young University
Ph.D. University of Utah
Diane Ward's Lab Page
Diane Ward's PubMed Literature Search
Molecular Biology Program
Membrane Trafficking and Iron Metabolism
My research has focused on two major areas. First, I study membrane trafficking specifically looking at vesicle formation and molecules involved in endocytic/secretory vesicle homeostasis. My lab, in collaboration with Dr. Ryan O’Connell (Pathology), has focused on identifying the mechanisms that regulate exosome formation, release and delivery in vivo and in vitro and how exosomes modulate immune response. I have also focused my efforts on biochemically and genetically dissecting the mechanisms of vesicle fusion with lysosomes, specifically examining how the loss of the protein Lyst (mutant in Chediak Higashi Syndrome) affects lysosome size. We have utilized yeast, mammalian cells and mouse models to understand lysosome biology and membrane trafficking. Understanding lysosome biology has led to the study of how iron is stored in lysosomes and how it is transported out of lysosomes upon iron demand. This research connects my membrane trafficking research and the second focus in my lab.
The second area of research I have focused on is iron metabolism. Iron is an element required by virtually all organisms. The transport of iron into cells and within cells requires appropriate membrane trafficking. Our studies on iron metabolism have focused primarily on the mechanisms that regulate iron import/export in the model organism Saccharomyces cerevisiae with the goal of identifying homologues in higher eukaryotes. Malregulation of iron metabolism in humans leads to anemia when iron uptake into the body is inadequate and iron overload disease when iron transport cannot be regulated. Work in the lab has led to a mechanistic understanding of both iron overload and the anemia of chronic disease. Mammalian iron metabolism is regulated by a hormone, termed hepcidin, which is secreted by the liver in response to inflammation and iron. We discovered that this hormone binds to the iron exporter Ferroportin and induces the internalization and degradation of Ferroportin resulting in retention of iron in cells. We have identified mitochondrial iron transporters Mitoferrin1 and Mitoferrin2 and partner proteins Abcb10 involved in mitochondrial iron homeostasis. We have generated conditional knockout mice for Mitoferrin1 and Mitoferrin2 and are determining their role in development, red blood cell formation and organ physiology.
Image Above: Right hand column confocal images of Hela cells silenced for Nonspecific,
Mon1a or Dynein Heavy Chain1. Red is ERGIC-53 (ER-Golgi intermediate compartment),
blue is BiP (ER) and green is GalNAc-T2 GFP (Golgi). Bagley, DC, Paradkar, PN, Durchfort,
N, Kaplan, J and Ward, DM (2012) Mon1a protein acts in trafficking through the secretory
apparatus. J Biol Chem 287:25577-25588
Seguin, A, Takahashi-Makise, N, Yien, YY, Huston, NC, Whitman, JC, Musso, G, Wallace, JA, Bradley, T, Bergonia, H, Kafina, MD, Matsumoto, M, Igarashi, K, Phillips, JD, Paw, BH, Kaplan, J and Ward, DM. (2017). Reductions in the mitochondrial ABC transporter Abcb10 affect the transcriptional profile of heme biosynthesis genes. J. Biol. Chem. (in press).
Li, L, Kaplan, J and Ward, DM. (2017). The glucose sensor Snf1 and the transcription factors Msn2 and Msn4 regulate transcription of the vacuolar iron importer gene CCC1 and iron resistance in yeast. J. Biol. Chem. (in press).
Feldkamp, ML, Ward, DM, Pysher, TJ and Chambers, CT. (2017). Chlamydia trachomatis is responsible for lipid vacuolation in the amniotic epithelium of fetal gastroschisis. Birth Defects Res. (in press).
Yaish, HM, Farrell, CP, Christensen, RD, MacQueen, BC, Jackson, LK, Trochez-Enciso, J, Kaplan, J, Ward, DM, Salah WK, Phillips JD. (2017) Two novel mutations in TMPRSS6 associated with iron-refractory iron deficiency anemia in a mother and child. Blood Cells Mol Dis. 65:38-40. PMID:28460265.
MacQueen, BC, Christensen, RD, Ward, DM, Yaish, HM, Bennett, ST, O’Brien, EA, Sheffield, MJ, Baer, VL, Now, GL, Weaver Lewis, K, Fleming, RE and Kaplan, J. (2016). The iron status at birth of neonates who are “at risk” for developing iron deficiency; a pilot study. J. of Perinatology. 1-5. PMID:27977019.
Shrestha, R, Kaplan, J and Ward, DM. (2016). Conventional and Secretory Lysosomes: Encyclopedia of Cell Biology. Vol.2:225-234.
- Alexander, M, Hu, R, Runtsch, MC, Kagele, DA, Mosbruger, TL, Tolmachova, T, Seabra, MC, Round, JL, Ward, DM, and O'Connell, RM. (2015). Exosome-delivered microRNAs modulate the inflammatory response to endotoxin. Nat Commun. 6:7321. PMID: 26084661
- Yien, YY, Robledo, RF, Schultz, IJ, Takahashi-Makise, N, Gwynn, B, Bauer DE, Dass, A, Yi, G, Li, L, Hildick-Smith, GJ, Cooney, JD, Pierce, EL, Mohler, K, Dailey, TA, Miyata, N, Kingsley, PD, Garone, C, Hattangadi, SM, Huang, H, Chen, W, Keenan, EM, Shah, DI, Schlaeger, TM, DiMauro, S, Orkin, SH, Cantor, AB, Palis, J, Koehler, CM, Lodish, HF, Kaplan, J, Ward, DM, Dailey, HA, Phillips, JD, Peters, LL and Paw, BH. (2014). TMEM14C is required for erythroid mitochondrial heme metabolism. J. Clin. Inv. 124:4294-4304. PMID:25157825
- Ben-Othman, R, Flannery, A, Miguel, Ward, DM, Kaplan, J and Andrews, NW. (2014). Leishmania-mediated inhibition of iron export promotes parasite replication in macrophages. PLOS Pathogens. 10:1-13. PMID:24497831
- Chung, J, Anderson, SA, Gwynn, B, Deck, KM, Chen, MJ, Langer, NB, Shaw, GC, Huston, NC, Boyer, LA, Datta, S, Paradkar, PN, Li, L, Wei, Z, Lambert, AJ, Sahr, K, Wittig, JG, Chen, W, Lu, W, Galy, B, Schlaeger, TM, Hentze, MW, Ward, DM, Kaplan, J, Eisenstein, RS, Peters, LL and Paw, BH. (2014). Iron Regulatory Protein-1 protects against mitoferrin1-deficient Porphyria. J. Biol. Chem. 289:7835-7843. PMID:24509859
- Li, l, Miao, R, Jia, X, Ward, DM and Kaplan, J. (2014). Expression of the yeast cation diffusion facilitators Mmt1 and Mmt2 affects mitochondrial and cellular iron homeostasis: evidence for mitochondrial iron export. J. Biol. Chem. 289(24):17132-17141. PMID:24798331
- Kaplan, J and Ward, DM. (2013). The essential nature of iron usage and regulation: variations on a theme. Curr. Biol. 15:R642-6. PMID:23928078
- Kaplan, J and Ward, DM. (2013). Molecular Genetics of Chediak-Higashi Syndrome. Invited review. eLS. September DOI: 10.1002/9780470015902.a0024308
- Chen, C, Garcia-Santos, D, Ishikawa, Y, Seguin, A, Li, L, Fegan, KH, Hildick-Smith, GJ, Shah, DI, Cooney, JD, Chen, W, King, MJ, Yien, YY, Schultz, IJ, Anderson, H, Dalton, AJ, Freedman, ML, Kingsley, PD, Palis, J, Hattangadi, SM, Lodish, HF, Ward, DM, Kaplan, J, Maeda, T, Ponka, P and Paw, BH. (2013). Snx3 regulates recycling of the transferrin receptor and iron assimilation. Cell Metab. 17(3):343-52. PMID:23416069
- White, C, Yuan, X, Schmidt, P, Bresciani, E, Campagna, D, Hall, C, Ward, DM, Liu, P, Fleming, M and Hamza, I. (2013). HRG-1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis. Cell Metab. 17:261-270. PMID:23395172
- Bagley, DC, Paradkar, PN, Durchfort, N, Kaplan, J and Ward, DM. (2012). Mon1a protein acts in trafficking through the secretory apparatus. J. Biol. Chem. 287:25577-25588. PMID:22665492
- Durchfort, N, Verhoef, S, Vaughn, MB, Shrestha, R, Adam, D, Kaplan, J and Ward, DM. (2012). The enlarged lysosomes in beige cells result from decreased lysosome fission and not increased lysosome fusion. Traffic. 13:108-119. PMID:21985285
- Li, l, Miao, R, Bertram, S, Jia, X, Ward, DM and Kaplan, J. (2012). A role for iron-sulfur clusters in the regulation of Yap5-dependent high iron transcriptional responses in yeast. J. Biol. Chem. 287:35709-35721. PMID:22915593
- Shah, DI, Takahashi-Makise, N, Cooney, JD, Seguin, A, Li, L, Schultz, IJ, Pierce, EL, Narla, A, Hattangadi, SM, Langer, NB, Chen W, Dailey, TA, Medlock, AE, Hurst, SN, Faccenda, D, Wiwczar, JM, Vogin, G, Brugnara, C, Zhou, Y, Ward, DM, Ebert BL, Campanella, M, Danial, NN, Dailey, HA, Kaplan, J and Paw, BH. (2012). Mitochondrial Atpif1 regultes heme synthesis in developing erythroblasts. Nature. 491:608-612. PMID:23135403