Ferritin – Regulation of Levels

  • To maintain iron homeostasis, ferritin expression is tightly regulated.1
  • The regulation of ferritin expression involves transcriptional and post-transcriptional mechanisms.
  • Posttranscriptional pathways of ferritin regulation:
    • Regulation of ferritin levels takes place primarily at the level of the cytoplasmic 5′-untranslated mRNA.
    • Iron-mediated posttranscriptional regulation:
      • Ferritin production is tightly controlled by iron levels at the level of translation.
      • Post-transcriptional iron-dependent regulation is based upon the interaction of iron regulatory proteins 1 and 2 (IRP1, IRP2) with the iron responsive elements (IRE) on ferritin mRNAs.2
        • Ferritin heavy chain (FTH) and ferritin light chain (FTL) mRNA contain an iron response element (IRE) in their 5′ untranslated region (UTR).3
        • The IRE is a regulatory stem–loop structure that when bound by iron regulatory proteins 1 or 2 (IRP1 or IRP2) suppresses mRNA translation:45
        • When IRE is not bound by IRP, translation of ferritin occurs. Thus, IRPs have an inhibitory effect on the synthesis of ferritin:
        • When iron is in low supply, IRP affinity for the IRE is increased, resulting in translational repression of ferritin heavy and light chains.6
        • Conversely, in the presence of elevated iron levels, IRP1 and IRP2 do not bind as readily to IRE and ferritin mRNA synthesis is increased.7
      • The importance of the IRE in ferritin regulation is evidenced by the finding that patients with the autosomal dominant disorder, hereditary hyperferritinaemia-cataract syndrome (HHCS), have point mutations in the IRE of ferritin L mRNA, leading to the constitutive activation of ferritin L translation and high serum ferritin in the absence of iron excess.8
    • Posttranscriptional regulation by other signals:
      • Interleukin (IL)-1β does not increase ferritin mRNA, but facilitates ferritin translation by binding to a G and C rich region in the 5′ UTR.9
      • IL-10 induces ferritin expression at a post-transcriptional level, but the mechanism is unknown.
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  • Transcriptional pathways of ferritin regulation:
    • Ferritin transcription has been shown to be induced by:10
      • Oxidative stress
      • Tumor necrosis factor (TNF)-α
      • IFN-γ
      • IL-1α
      • IL-6
    • Proinflammatory cytokines appear to selectively or at least preferentially induce the H chain of ferritin via nuclear factor (NF)-κB, Nrf2 and JunD pathway.1112
    • The regulatory elements in the murine gene that respond to cytokines have been mapped in detail, and the DNA binding proteins that mediate this response have been identified:13
      • Ferritin H is regulated by TNFα through a cis-acting region (FER2) located 4.8 kb upstream of the transcriptional start site that binds the transcription factor NFκB
      • Two of the multiple NFκB subunits are specifically involved in this binding, p50 and p65.
      • They bind to an NFκB full consensus sequence and to an adjacent NFκB core sequence.
      • Both sequences are necessary for maximal ferritin H induction by TNFα
      • However, most stimuli directing ferritin synthesis in inflammation cause upregulation of H subunit
Mouse and human ferritin H genes. In the murine gene, regulatory regions reside between 4 kb and 5 kb distal to the transcriptional start site; in the human gene, regulatory regions are just 5′ of the TATA box. However, similar sequence motifs and binding proteins suggest similar functional regulation of these genes. IF1 has not been definitively identified as binding to the G-fer region of the human ferritin H gene. Source.
  • Q: What happens when opposing forces converge on ferritin regulation in a patient with concomitant iron deficiency and inflammation?
  • A: Repressive effect of iron deficiency on translation tends to win out over the inductive effect of inflammatory cytokines on transcription.
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