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The actin binding protein profilin 2 is a novel regulator of iron homeostasis

Sara Luscieti, Bruno Galy, Lucia Gutierrez, Michael Reinke, Jorge Couso, Maya Shvartsman, Antonio Di Pascale, Walter Witke, Matthias W. Hentze, Pietro Pilo Boyl and Mayka Sanchez

Key points

  • Pfn2 mRNA has a functional and conserved 3' UTR Iron-Responsive Element (IRE).

  • Pfn2 knock-out mice display an iron phenotype with iron accumulation in specific areas of the brain and depletion of liver iron stores.

Abstract

Cellular iron homeostasis is controlled by the iron regulatory proteins (IRPs) 1 and 2 that bind cis-regulatory iron-responsive elements (IRE) on target mRNAs. We identified the profilin2 (Pfn2) mRNA, which encodes an actin binding protein involved in endocytosis and neurotransmitters release, as a novel IRP-interacting transcript and studied its role in iron metabolism. Combination of EMSA experiments and bioinformatic analyses led to the identification of an atypical and conserved IRE in the 3' untranslated region of Pfn2 mRNA. Pfn2 mRNA levels were significantly reduced in duodenal samples from mice with intestinal-IRP ablation, suggesting that IRPs exert a positive effect on Pfn2 mRNA expression in vivo. Over-expression of Pfn2 in HeLa and Hepa1-6 cells reduced their metabolically active iron pool. Importantly, Pfn2-deficient mice showed iron accumulation in discrete areas of the brain (olfactory bulb, hippocampus and midbrain) and reduction of the hepatic iron store without anaemia. In spite of low liver iron levels, hepatic hepcidin expression remained high, likely due to compensatory activation of Hepcidin by mild inflammation. Splenic ferroportin was increased probably to sustain hematopoiesis. Overall, our results indicate that Pfn2 expression is controlled by the IRPs in vivo and that Pfn2 contributes to maintaining iron homeostasis in cell lines and mice.

  • Submitted November 30, 2016.
  • Accepted July 30, 2017.