Iron (Fe) is an essential element that serves as a biochemical co-factor for a wide variety of enzymes and proteins that function in oxygen transport, mitochondrial oxidative phosphorylation, DNA replication and repair, intermediary metabolism, lipid metabolism, chromatin modification and a host of other critical physiological processes. Fe deficiency is the most common nutritional deficiency on earth, with health consequences that include anemia, delayed growth and development, abnormal motor and cognitive function, decreased immune function, thermoreguatory defects, fatigue and decreased work performance. While Fe deficiency leads to severe health consequences, the detailed molecular mechanisms that allow graded responses to a range of severity of Fe deficiency are not well understood. This proposal describes avenues of investigation to understand fundamental mechanisms whereby eukaryotic cells respond and adapt to Fe deficiency. The first specific aim outlines experiments to decipher the mechanisms by which the yeast Cth1 and Cth2 proteins differentially target mRNAs for degradation in response to Fe deficiency, leading to cellular metabolic adaptation to allow cells to cope with reduced Fe availability. The second specific aim describes experiments to understand how expression of the Cth1 and Cth2 proteins is exquisitely fine-tuned in response to Fe deficiency, the physiological importance of this regulation with respect to Fe homeostasis and its potential link to changes in cell cycle progression. Given the common occurrence of Fe deficiency and its disproportionate affects on the health of women and children, the studies outlined in this application will provide fundamentally important information on the mechanisms by which cells homeostatically respond to Fe deficiency.
Fe deficiency is the most common nutritional deficiency on earth, with health consequences that include anemia, delayed growth and development, abnormal motor and cognitive function, decreased immune function, thermoregulatory defects, fatigue and decreased work performance. Given the common occurrence of Fe deficiency and its disproportionate affects on the health of women and children, the studies outlined in this application will provide fundamentally important information on the mechanisms by which cells adapt to Fe deficiency.
|Festa, Richard A; Helsel, Marian E; Franz, Katherine J et al. (2014) Exploiting innate immune cell activation of a copper-dependent antimicrobial agent during infection. Chem Biol 21:977-87|
|Ohrvik, Helena; Thiele, Dennis J (2014) How copper traverses cellular membranes through the mammalian copper transporter 1, Ctr1. Ann N Y Acad Sci 1314:32-41|
|Palacios, Oscar; Espart, Anna; Espin, Jordi et al. (2014) Full characterization of the Cu-, Zn-, and Cd-binding properties of CnMT1 and CnMT2, two metallothioneins of the pathogenic fungus Cryptococcus neoformans acting as virulence factors. Metallomics 6:279-91|
|Ding, Chen; Festa, Richard A; Chen, Ying-Lien et al. (2013) Cryptococcus neoformans copper detoxification machinery is critical for fungal virulence. Cell Host Microbe 13:265-76|
|Samanovic, Marie I; Ding, Chen; Thiele, Dennis J et al. (2012) Copper in microbial pathogenesis: meddling with the metal. Cell Host Microbe 11:106-15|
|Nevitt, Tracy; Ohrvik, Helena; Thiele, Dennis J (2012) Charting the travels of copper in eukaryotes from yeast to mammals. Biochim Biophys Acta 1823:1580-93|
|Beaudoin, Jude; Thiele, Dennis J; Labbe, Simon et al. (2011) Dissection of the relative contribution of the Schizosaccharomyces pombe Ctr4 and Ctr5 proteins to the copper transport and cell surface delivery functions. Microbiology 157:1021-31|
|Vergara, Sandra V; Puig, Sergi; Thiele, Dennis J (2011) Early recruitment of AU-rich element-containing mRNAs determines their cytosolic fate during iron deficiency. Mol Cell Biol 31:417-29|
|Nevitt, Tracy (2011) War-Fe-re: iron at the core of fungal virulence and host immunity. Biometals 24:547-58|
|Ding, Chen; Yin, Jun; Tovar, Edgar Mauricio Medina et al. (2011) The copper regulon of the human fungal pathogen Cryptococcus neoformans H99. Mol Microbiol 81:1560-76|
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