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

A Nandal, JC Ruiz, P Subramanian, S Ghimire-Rijal… - Cell metabolism, 2011 - cell.com
A Nandal, JC Ruiz, P Subramanian, S Ghimire-Rijal, RA Sinnamon, TL Stemmler, RK Bruick…
Cell metabolism, 2011cell.com
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 …
Summary
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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