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

Anjali Nandal, Julio C. Ruiz, Poorna Subramanian, Sudipa Ghimire-Rijal, Ruth Ann Sinnamon, Timothy L. Stemmler, Richard K. Bruick, Caroline C. Philpott

Research output: Contribution to journalArticlepeer-review

118 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)647-657
Number of pages11
JournalCell Metabolism
Volume14
Issue number5
DOIs
StatePublished - Nov 2 2011

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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