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Iron Drives T Helper Cell Pathogenicity by Promoting RNA-Binding Protein PCBP1-Mediated Proinflammatory Cytokine Production
Open accessAbstract
Iron deposition is frequently observed in human autoinflammatory diseases, but its functional significance is largely unknown. Here we showed that iron promoted proinflammatory cytokine expression in T cells, including GM-CSF and IL-2, via regulating the stability of an RNA-binding protein PCBP1. Iron depletion or Pcbp1 deficiency in T cells inhibited GM-CSF production by attenuating Csf2 3' untranslated region (UTR) activity and messenger RNA stability. Pcbp1 deficiency or iron uptake blockade in autoreactive T cells abolished their capacity to induce experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. Mechanistically, intracellular iron protected PCBP1 protein from caspase-mediated proteolysis, and PCBP1 promoted messenger RNA stability of Csf2 and Il2 by recognizing UC-rich elements in the 3' UTRs. Our study suggests that iron accumulation can precipitate autoimmune diseases by promoting proinflammatory cytokine production. RNA-binding protein-mediated iron sensing may represent a simple yet effective means to adjust the inflammatory response to tissue homeostatic alterations.
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“It was demonstrated that iron protects PCBP1 (Poly(RC)-binding protein 1), an RNA binding protein which stabilizes GMCSF mRNA, from caspase-mediated proteolysis thus leading to enhanced GMCSF production when iron levels are high within the T cell to drive inflammation (Wang et al., 2018).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Wang et al., 2018
In the citing paper
“In a recent investigation it could be demonstrated that iron was able to directly participate in inflammatory responses by promoting proinflammatory cytokine production in T helper cells via poly(rC)-binding protein 1 [133].”
From Iron in immune cell function and host defense (2021) · cites this paper as [133]
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Metadata
- Authors
- Wang, Z., Yin, W., Zhu, L., Li, J., Yao, Y., Chen, F., Sun, M., Zhang, J., Shen, N., Song, Y., & Chang, X.
- Affiliations
- Shanghai Jiao Tong University (CN)
- University of California San Diego (US)
- Corresponding author
- Chang, Xing
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 49
- Issue
- 1
- Pages
- 80-92.e7
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2810518168
- Cited by
- 156
- References
- 66
- Citations by year
- 2026: 14 · 2025: 15 · 2024: 28 · 2023: 26 · 2022: 31 · 2021: 20 · 2020: 13 · 2019: 8 · 2018: 1
- FWCI
- 7.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Funders
- MOST (31370858, 81671552)
- NSFC (13PJ1409300)
- SMSTC
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- iron accumulation, T helper cells, PCBP1, RNA-binding proteins, inflammatory cytokines, GM-CSF, interleukin-2, mRNA stability, 3' untranslated region, experimental autoimmune encephalomyelitis, multiple sclerosis, autoinflammatory disease, iron sensing, autoreactive T cells
- MeSH terms
- Iron Deficiencies, Animals, Binding Sites, Carrier Proteins, Cell Line, DNA-Binding Proteins, Encephalomyelitis, Autoimmune, Experimental, Female, T-Lymphocytes, Helper-Inducer, Humans, Iron, Multiple Sclerosis, Receptors, Transferrin, RNA Processing, Post-Transcriptional, RNA, Messenger, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Cytokines, RNA-Binding Proteins, 3' Untranslated Regions, RNA Stability, RNA, Small Interfering, Mice
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