Iron-regulatory proteins limit hypoxia-inducible factor-2α expression in iron deficiency
Abstract
Hypoxia stimulates erythropoiesis, the major iron-utilization pathway. We report the discovery of a conserved, functional iron-responsive element (IRE) in the 5' untranslated region of the messenger RNA encoding endothelial PAS domain protein-1, EPAS1 (also called hypoxia-inducible factor-2alpha, HIF2alpha). Via this IRE, iron regulatory protein binding controls EPAS1 mRNA translation in response to cellular iron availability. Our results uncover a regulatory link that permits feedback control between iron availability and the expression of a key transcription factor promoting iron utilization. They also show that an IRE that is structurally distinct from, for example, the ferritin mRNA IRE and that has been missed by in silico approaches, can mediate mechanistically similar responses.
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All HIFs contribute to transcriptional programs maintaining iron metabolism.
“Consistent with this, all HIFs contribute to transcriptional programs maintaining iron metabolism [[97], [98], [99]]”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [98]
Translation of EPAS1 (HIF-2α) mRNA is regulated by an iron-responsive element in its 5′ UTR, coupling HIF-2 activity to iron availability.
“Translation of EPAS1 (HIF-2α) mRNA is regulated by an iron-responsive element in its 5′ UTR, coupling HIF-2 activity to iron availability [[97], [98], [99]]”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [98]
The HIF2α mRNA contains an IRE in its 5'UTR.
“Indeed the HIF2α mRNA bears an IRE in its 5’UTR (Sanchez et al., 2007)”
From Iron Regulatory Proteins Mediate Host Resistance to Salmonella Infection (2015) · cites this paper as Sanchez et al., 2007
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- Authors
- Sanchez, M., Galy, B., Muckenthaler, M. U., & Hentze, M. W.
- Affiliations
- European Molecular Biology Laboratory (DE)
- Heidelberg University (DE)
- Corresponding author
- Muckenthaler, Martina U
- Hentze, Matthias W
- Venue
- Nature Structural & Molecular Biology
- Published
- 2007-04-08
- Volume
- 14
- Issue
- 5
- Pages
- 420-426
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- OpenAlex
- W2008376250
- Cited by
- 294
- References
- 51
- Citations by year
- 2026: 6 · 2025: 19 · 2024: 14 · 2023: 14 · 2022: 19 · 2021: 17 · 2020: 14 · 2019: 12 · 2018: 12 · 2017: 17 · 2016: 7 · 2015: 15 · 2014: 20 · 2013: 21 · 2012: 16
- FWCI
- 10.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- iron regulatory proteins, HIF-2α, EPAS1, iron-responsive element, iron deficiency, erythropoiesis, iron utilization, mRNA translation regulation, 5' untranslated region, iron availability
- MeSH terms
- Iron Deficiencies, Endothelial PAS Domain-Containing Protein 1, Gene Expression Regulation, HeLa Cells, Humans, RNA, Messenger, Transcription Factors, Iron Metabolism Disorders, Response Elements, Feedback, Physiological, Iron-Regulatory Proteins, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins
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