Mammalian cells express dozens of iron-containing proteins, yet little is known about the mechanism of metal ligand incorporation. Human poly (rC) binding protein 1 (PCBP1) is an iron chaperone that binds iron and delivers it to ferritin, a cytosolic iron storage protein. We have identified the iron-dependent prolyl hydroxylases (PHDs) and asparaginyl hydroxylase (FIH1) that modify hypoxia-inducible factor α(HIFα) as targets of PCBP1. Depletion of PCBP1 or PCBP2 in cells led to loss of PHD activity, manifested by reduced prolyl hydroxylation of HIF1α, impaired degradation of HIF1αthrough the VHL/proteasome pathway, and accumulation of active HIF1 transcription factor. PHD activity was restored in vitro by addition of excess Fe(II) or purified Fe-PCBP1, and PCBP1 bound to PHD2 and FIH1 in vivo. These data indicated that PCBP1 was required for iron incorporation into PHD and suggest a broad role for PCBP1 and 2 in delivering iron to cytosolic non-heme iron enzymes.

Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2012
Total Cost
$1,237,859
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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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