Activation of the HIF Prolyl Hydroxylase by the Iron Chaperones PCBP1 and PCBP2
Open accessAbstract
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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EGLN 1-3 activity and HIF-α stability are affected by iron availability and can be inhibited by Krebs cycle intermediates succinate and fumarate.
“As a result, EGLN 1–3 activity and HIF-α stability are affected by iron availability and can be inhibited by Krebs cycle intermediates, including succinate and fumarate, which compete with 2-oxoglutarate”
From Hypoxic control of metastasis (2016) · cites this paper as [19]
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References 32 · Cited by 204
- Authors
- Nandal, A., Ruiz, J. C., Subramanian, P., Ghimire-Rijal, S., Sinnamon, R. A., Stemmler, T. L., Bruick, R. K., & Philpott, C. C.
- Affiliations
- National Institutes of Health (US)
- The University of Texas Southwestern Medical Center (US)
- Wayne State University (US)
- Corresponding author
- Philpott, Caroline C.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2011-11
- Volume
- 14
- Issue
- 5
- Pages
- 647-657
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3361910
- OpenAlex
- W2006268101
- Cited by
- 204
- References
- 32
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 11 · 2023: 8 · 2022: 17 · 2021: 16 · 2020: 20 · 2019: 18 · 2018: 18 · 2017: 11 · 2016: 19 · 2015: 12 · 2014: 9 · 2013: 8 · 2012: 16
- FWCI
- 7.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA115962, R01CA115962)
- National Institute of Diabetes and Digestive and Kidney Diseases (NIH DK068139, R01DK068139)
- National Center for Research Resources (C06RR015437, C06 RR 15437-01))
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Keywords
- PCBP1, PCBP2, iron chaperone, prolyl hydroxylase, hypoxia-inducible factor alpha, iron incorporation, non-heme iron enzymes, ferritin, metalloproteins, hypoxia signaling
- MeSH terms
- Hypoxia, Cell Line, DNA-Binding Proteins, Enzyme Activation, Ferritins, Half-Life, Humans, Hydroxylation, Iron, Luciferases, Procollagen-Proline Dioxygenase, Protein Binding, Signal Transduction, Gene Expression, RNA-Binding Proteins, Ion Transport, Genes, Reporter, Molecular Chaperones, Heterogeneous-Nuclear Ribonucleoproteins, RNA, Small Interfering, Proteasome Endopeptidase Complex, Hypoxia-Inducible Factor 1, alpha Subunit
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