Iron regulatory proteins control a mucosal block to intestinal iron absorption
Open accessAbstract
Mammalian iron metabolism is regulated systemically by the hormone hepcidin and cellularly by iron regulatory proteins (IRPs) that orchestrate a posttranscriptional regulatory network. Through ligand-inducible genetic ablation of both IRPs in the gut epithelium of adult mice, we demonstrate that IRP deficiency impairs iron absorption and promotes mucosal iron retention via a ferritin-mediated "mucosal block." We show that IRP deficiency does not interfere with intestinal sensing of body iron loading and erythropoietic iron need, but rather alters the basal expression of the iron-absorption machinery. IRPs thus secure sufficient iron transport across absorptive enterocytes by restricting the ferritin "mucosal block" and define a basal set point for iron absorption upon which IRP-independent systemic regulatory inputs are overlaid.
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Removing both IRPs together strongly increases FPN, FTH1, and FTL1 and lowers TFR1 protein and mRNA.
“the simultaneous ablation of both IRPs causes a marked increase in FPN, FTH1, and FTL1 expression (Figure 1A, left), most likely due to translational derepression of the corresponding mRNAs (Galy et al., 2013) and to a minor extent to increased mRNA expression (Figure 1A, right); double IRP deficiency expectedly decreases TFR1 protein and mRNA levels (Figure 1A).”
From Iron Regulatory Proteins Mediate Host Resistance to Salmonella Infection (2015) · cites this paper as Galy et al., 2013
Loss of IRPs causes HIF2α overexpression.
“However, IRP ablation leads to HIF2α overexpression (Galy et al., 2013)”
From Iron Regulatory Proteins Mediate Host Resistance to Salmonella Infection (2015) · cites this paper as Galy et al., 2013
Iron accumulates in IrpLyzCre(+) cells despite lower TFR1 and higher FPN, possibly because it is sequestered in excess ferritin.
“Iron loading in IrpLyzCre(+) cells occurs in spite of reduction of the TFR1 iron uptake molecule and stimulation of the FPN iron exporter (Figure 1), and could possibly reflect sequestration of the metal into the overabundant ferritin (Galy et al., 2013).”
From Iron Regulatory Proteins Mediate Host Resistance to Salmonella Infection (2015) · cites this paper as Galy et al., 2013
IRPs negatively regulate ferritin translation to prevent inappropriate iron sequestration in enterocytes.
“IRPs negatively regulate Ft translation to prevent inappropriate iron sequestration in enterocytes. 51 , 52”
From The battle for iron in enteric infections (2020) · cites this paper as [51]
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- Authors
- Galy, B., Ferring-Appel, D., Becker, C., Gretz, N., Gröne, H.-J., Schümann, K., & Hentze, M. W.
- Affiliations
- European Molecular Biology Laboratory (DE)
- Technical University of Munich (DE)
- Heidelberg University (DE)
- German Cancer Research Center (DE)
- Corresponding author
- Galy, Bruno
- Hentze, Matthias W.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 3
- Issue
- 3
- Pages
- 844-857
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W1964982621
- Cited by
- 98
- References
- 49
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 3 · 2023: 7 · 2022: 5 · 2021: 3 · 2020: 14 · 2019: 4 · 2018: 6 · 2017: 10 · 2016: 5 · 2015: 11 · 2014: 16 · 2013: 3
- FWCI
- 8.37
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Technische Universität München
- Cilag
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Micronutrient Interactions and Effects
- Keywords
- iron regulatory proteins, intestinal iron absorption, hepcidin, ferritin, iron metabolism, enterocytes, post-transcriptional regulation, erythropoiesis, iron homeostasis
- MeSH terms
- Ferroportin, Animals, Ferritins, Intestinal Absorption, Iron, Mutation, Transcription, Genetic, Ion Transport, Enterocytes, Cation Transport Proteins, Iron-Regulatory Proteins, Mice
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