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Translational regulation via iron‐responsive elements by the nitric oxide/NO‐synthase pathway.
Open accessAbstract
Nitric oxide (NO) produced from L-arginine by NO synthases (NOS) is a transmitter known to be involved in diverse biological processes, including immunomodulation, neurotransmission and blood vessel dilatation. We describe a novel role of NO as a signaling molecule in post-transcriptional gene regulation. We demonstrate that induction of NOS in macrophage and non-macrophage cell lines activates RNA binding by iron regulatory factor (IRFs), the central trans regulator of mRNAs involved in cellular iron metabolism. NO-induced binding of IRF to iron-responsive elements (IRE) specifically represses the translation of transfected IRE-containing indicator mRNAs as well as the biosynthesis of the cellular iron storage protein ferritin. These findings define a new biological function of NO and identify a regulatory connection between the NO/NOS pathway and cellular iron metabolism.
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“Nonetheless, these highly reactive intermediates execute their microbicidal activity by oxidative destruction of membrane lipids, DNA, thiol and tyrosine residues, whereas NO can exert toxicity by directly targeting iron sulfur cluster of central metabolic enzymes (57, 58, 70–72).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [71]
In the citing paper
“Both ROS and RNS have high affinity toward Fe 2+ in the prosthetic heme groups or Fe-sulfur clusters of a variety of proteins [79,80].These include IRPs, to which NO can bind and modulate their stability as well as activity [81,82], resulting in IRE-mediated regulation of Fe metabolism [58,66,[81][82][83][84][85][86].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [81]
In the citing paper
“IFNc also induces the expression of iNOS/NOS2 [78], via a mechanism regulated at a transcriptional level by the activation of the signal transducers and activators of transcription (STAT) family of transcription factors (Fig 2).As described above, the NO produced by iNOS/NOS2 regulates the binding affinities of IRP toward target IRE in genes such as transferrin receptor (TfR) and ferritin, inhibit”
From The Iron age of host–microbe interactions (2015) · cites this paper as [81]
In the citing paper
“By this mechanism NO also affects cellular iron homeostasis via translational regulation of iron genes via iron regulatory proteins (IRP) thereby controlling ferritin expression and the availability of iron for microbes”
From Iron in immune cell function and host defense (2021) · cites this paper as [57]
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References 62 · Cited by 389
Metadata
- Authors
- Weiss, G., Goossen, B., Doppler, W., Fuchs, D., Pantopoulos, K., Werner‐Felmayer, G., Wachter, H., & Hentze, M. W.
- Affiliations
- European Molecular Biology Laboratory (DE)
- Venue
- The EMBO Journal
- Published
- 1993-09-01
- Volume
- 12
- Issue
- 9
- Pages
- 3651-3657
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC413641
- OpenAlex
- W88281208
- Cited by
- 389
- References
- 62
- Citations by year
- 2025: 1 · 2024: 6 · 2023: 4 · 2022: 3 · 2021: 4 · 2020: 8 · 2019: 3 · 2018: 5 · 2017: 1 · 2016: 3 · 2015: 6 · 2014: 9 · 2013: 6 · 2012: 8
- FWCI
- 22.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Austrian Science Fund
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
- Keywords
- nitric oxide, nitric oxide synthase, iron-responsive element, post-transcriptional regulation, protein synthesis inhibition, macrophages, L-arginine
- MeSH terms
- Amino Acid Oxidoreductases, Animals, Arginine, Base Sequence, Cell Line, Leukemia, Erythroblastic, Acute, Humans, Iron, Macrophage Activation, Macrophages, Models, Biological, Molecular Sequence Data, Nitric Oxide, Oligodeoxyribonucleotides, Recombinant Fusion Proteins, RNA, Messenger, Protein Biosynthesis, Tumor Cells, Cultured, RNA Probes, Chloramphenicol O-Acetyltransferase, Gene Expression Regulation, Enzymologic, RNA-Binding Proteins, Nitric Oxide Synthase, Iron-Regulatory Proteins, Mice
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