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

Immunity. 2018 Jul 17;49(1):80-92.e7. doi: 10.1016/j.immuni.2018.05.008. Epub 2018 Jun 26.

Abstract

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.

Keywords: 3′ UTR; CLIP; EAE; GM-CSF; PCBP1; RNA; RNA-binding protein; T cells; iron; post-transcription regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Binding Sites
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cytokines / biosynthesis*
  • Cytokines / genetics
  • DNA-Binding Proteins
  • Encephalomyelitis, Autoimmune, Experimental / metabolism*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Female
  • Humans
  • Iron / agonists
  • Iron / deficiency
  • Iron / metabolism*
  • Mice
  • Multiple Sclerosis / metabolism
  • Multiple Sclerosis / pathology
  • RNA Processing, Post-Transcriptional
  • RNA Stability / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Receptors, Transferrin / deficiency
  • T-Lymphocytes, Helper-Inducer / metabolism*
  • T-Lymphocytes, Helper-Inducer / pathology*
  • T-Lymphocytes, Helper-Inducer / transplantation

Substances

  • 3' Untranslated Regions
  • Carrier Proteins
  • Csf2ra protein, mouse
  • Cytokines
  • DNA-Binding Proteins
  • Pcbp1 protein, mouse
  • RNA, Messenger
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Receptors, Transferrin
  • Tfrc protein, mouse
  • Iron