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Τρίτη 26 Ιουνίου 2018

Iron Drives T Helper Cell Pathogenicity by Promoting RNA-Binding Protein PCBP1-Mediated Proinflammatory Cytokine Production

Publication date: Available online 26 June 2018
Source:Immunity
Author(s): Zhizhang Wang, Weijie Yin, Lizhen Zhu, Jia Li, Yikun Yao, Feifei Chen, Mengmeng Sun, Jiayuan Zhang, Nan Shen, Yan Song, Xing Chang
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.

Graphical abstract

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Teaser

Iron accumulation is observed in the brain of patients with neuroinflammatory diseases, yet its functional significance is poorly understood. Wang et al. demonstrate that iron promotes T cell pathogenicity by protecting RNA-binding protein PCBP1 from proteolysis, thereby promoting PCBP1-mediated stabilization of GM-CSF mRNA. These findings indicate that iron homeostasis can be targeted to suppress pathogenic T cells for treatment of neuroinflammatory diseases.


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