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 journalArticle

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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

Fingerprint

Prolyl Hydroxylases
Iron
Hypoxia
Proteasome Endopeptidase Complex
Hydroxylation
Ferritins
Mixed Function Oxygenases
Proteins
Transcription Factors
Metals
Ligands

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Nandal, A., Ruiz, J. C., Subramanian, P., Ghimire-Rijal, S., Sinnamon, R. A., Stemmler, T. L., ... Philpott, C. C. (2011). Activation of the HIF prolyl hydroxylase by the iron chaperones PCBP1 and PCBP2. Cell Metabolism, 14(5), 647-657. https://doi.org/10.1016/j.cmet.2011.08.015

Activation of the HIF prolyl hydroxylase by the iron chaperones PCBP1 and PCBP2. / Nandal, Anjali; Ruiz, Julio C.; Subramanian, Poorna; Ghimire-Rijal, Sudipa; Sinnamon, Ruth Ann; Stemmler, Timothy L.; Bruick, Richard K.; Philpott, Caroline C.

In: Cell Metabolism, Vol. 14, No. 5, 02.11.2011, p. 647-657.

Research output: Contribution to journalArticle

Nandal, A, Ruiz, JC, Subramanian, P, Ghimire-Rijal, S, Sinnamon, RA, Stemmler, TL, Bruick, RK & Philpott, CC 2011, 'Activation of the HIF prolyl hydroxylase by the iron chaperones PCBP1 and PCBP2', Cell Metabolism, vol. 14, no. 5, pp. 647-657. https://doi.org/10.1016/j.cmet.2011.08.015
Nandal A, Ruiz JC, Subramanian P, Ghimire-Rijal S, Sinnamon RA, Stemmler TL et al. Activation of the HIF prolyl hydroxylase by the iron chaperones PCBP1 and PCBP2. Cell Metabolism. 2011 Nov 2;14(5):647-657. https://doi.org/10.1016/j.cmet.2011.08.015
Nandal, Anjali ; Ruiz, Julio C. ; Subramanian, Poorna ; Ghimire-Rijal, Sudipa ; Sinnamon, Ruth Ann ; Stemmler, Timothy L. ; Bruick, Richard K. ; Philpott, Caroline C. / Activation of the HIF prolyl hydroxylase by the iron chaperones PCBP1 and PCBP2. In: Cell Metabolism. 2011 ; Vol. 14, No. 5. pp. 647-657.
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