Article

Activation of the HIF prolyl hydroxylase by the iron chaperones PCBP1 and PCBP2

Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Cell metabolism (Impact Factor: 17.57). 11/2011; 14(5):647-57. DOI: 10.1016/j.cmet.2011.08.015
Source: PubMed

ABSTRACT

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 HIF1α through 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 nonheme iron enzymes.

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    • "The activity of FIH1, also an iron- and oxygen-dependent HIF1α regulator, is dependent on PCBP1 as well (Nandal et al., 2011). Cells depleted of PCBP1 exhibit increased expression of a reporter construct repressed by FIH1, and FIH1 was detected in a complex with PCBP1 in iron-treated cells. "
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    • "This scenario might require additional, target-specific metallochaperones for transfer and insertion of the iron. Only PCBP1 and PCBP2 of mammals have been identified as iron-specific chaperones for metal ion assembly into ferritin and the hypoxia-inducible factor prolyl hydroxylase (Shi et al., 2008; Nandal et al., 2011). Alternatively , Grx3 might operate at the metal insertion step by preparing the target proteins for accepting the iron ions. "
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