title: Activation of the HIF prolyl hydroxylase by the iron chaperones PCBP1 and PCBP2.
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.
authors: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Anjali
authors: A
authors: Nandal
authors: Julio C
authors: JC
authors: Ruiz
authors: Poorna
authors: P
authors: Subramanian
authors: Sudipa
authors: S
authors: Ghimire-Rijal
authors: Ruth Ann
authors: RA
authors: Sinnamon
authors: Timothy L
authors: TL
authors: Stemmler
authors: Richard K
authors: RK
authors: Bruick
authors: Caroline C
authors: CC
authors: Philpott
mesh_terms: D002460:Cell Line; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D005293:Ferritins / Q000378:metabolism; D015870:Gene Expression; D017930:Genes, Reporter; D006207:Half-Life; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D017136:Ion Transport / Q000502:physiology*; D007501:Iron / Q000378:metabolism*; D008156:Luciferases / Q000032:analysis; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018832:Molecular Chaperones; C094604:PCBP1 protein, human; C501903:PCBP2 protein, human; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D005293:Ferritins; D007501:Iron; D008156:Luciferases; D011393:Procollagen-Proline Dioxygenase; D046988:Proteasome Endopeptidase Complex