The mechanisms through which iron-dependent enzymes receive their metal cofactors are largely unknown. Poly r(C) Binding Protein 1 (PCBP1) is an iron chaperone for ferritin;both PCBP1 and its paralog PCBP2 are required for iron delivery to the prolyl hydroxylase that regulates HIF1. Here we show that PCBP2 is also an iron chaperone for ferritin. Co-expression of PCBP2 and human ferritins in yeast activated the iron deficiency response and increased iron deposition into ferritin. Depletion of PCBP2 in Huh7 cells diminished iron incorporation into ferritin. Both PCBP1 and PCBP2 were co-immunoprecipitated with ferritin in HEK293 cells and expression of both PCBPs was required for ferritin complex formation in cells. PCBP1 and 2 exhibited high-affinity binding to ferritin in vitro. Mammalian genomes encode 4 PCBPs, including the minimally expressed PCBPs 3 and 4. Expression of PCBP3 and 4 in yeast activated the iron deficiency response, but only PCBP3 exhibited strong interactions with ferritin. Expression of PCBP1 and ferritin in an iron sensitive, ccc1 yeast strain intensified the toxic effects of iron, while expression of PCBP4 protected the cells from iron toxicity. Thus, PCBP1 and 2 form a complex for iron delivery to ferritin and all PCBPs may share iron chaperone activity.

Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2013
Total Cost
$1,820,150
Indirect Cost
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State
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Philpott, Caroline C; Ryu, Moon-Suhn; Frey, Avery et al. (2017) Cytosolic iron chaperones: Proteins delivering iron cofactors in the cytosol of mammalian cells. J Biol Chem 292:12764-12771
Ryu, Moon-Suhn; Zhang, Deliang; Protchenko, Olga et al. (2017) PCBP1 and NCOA4 regulate erythroid iron storage and heme biosynthesis. J Clin Invest 127:1786-1797
Frey, Avery G; Palenchar, Daniel J; Wildemann, Justin D et al. (2016) A Glutaredoxin-BolA Complex Serves as an Iron-Sulfur Cluster Chaperone for the Cytosolic Cluster Assembly Machinery. J Biol Chem :
Yabe-Wada, Toshiki; Matsuba, Shintaro; Takeda, Kazuya et al. (2016) TLR signals posttranscriptionally regulate the cytokine trafficking mediator sortilin. Sci Rep 6:26566
Li, Fengmin; Bullough, Kimberly Z; Vashisht, Ajay A et al. (2016) Poly(rC)-Binding Protein 2 Regulates Hippo Signaling To Control Growth in Breast Epithelial Cells. Mol Cell Biol 36:2121-31
Philpott, Caroline C; Protchenko, Olga (2016) Fungal physiology: Robbing the bank of haem iron. Nat Microbiol 1:16179
Frey, Avery G; Nandal, Anjali; Park, Jong Hwan et al. (2014) Iron chaperones PCBP1 and PCBP2 mediate the metallation of the dinuclear iron enzyme deoxyhypusine hydroxylase. Proc Natl Acad Sci U S A 111:8031-6
Philpott, Caroline C; Ryu, Moon-Suhn (2014) Special delivery: distributing iron in the cytosol of mammalian cells. Front Pharmacol 5:173
Philpott, Caroline C (2014) Pumping iron. Elife 3:e03997
Cyert, Martha S; Philpott, Caroline C (2013) Regulation of cation balance in Saccharomyces cerevisiae. Genetics 193:677-713

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