Regnase-1 Maintains Iron Homeostasis via the Degradation of Transferrin Receptor 1 and Prolyl-Hydroxylase-Domain-Containing Protein 3 mRNAs

• Published in: Cell reports (Cambridge) Vol. 19; no. 8; pp. 1614 - 1630
• Main Authors: Yoshinaga, Masanori, Nakatsuka, Yoshinari, Vandenbon, Alexis, Ori, Daisuke, Uehata, Takuya, Tsujimura, Tohru, Suzuki, Yutaka, Mino, Takashi, Takeuchi, Osamu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23-05-2017; Elsevier
• Subjects: anemia; Anemia - metabolism; Anemia - pathology; Animals; Antigens, CD - genetics; Antigens, CD - metabolism; Basic Helix-Loop-Helix Transcription Factors - metabolism; Duodenum - metabolism; endonuclease; Ferritins - metabolism; HIF2α; Homeostasis; Iron - metabolism; Mice; mRNA degradation; Procollagen-Proline Dioxygenase - metabolism; Promoter Regions, Genetic - genetics; Receptors, Transferrin - genetics; Receptors, Transferrin - metabolism; Response Elements - genetics; Ribonucleases - deficiency; Ribonucleases - metabolism; RNA Stability; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transcription, Genetic; transferrin receptor; iron metabolism; endonuclease; transferrin receptor; mRNA degradation; HIF2α; anemia
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.05.009

Iron metabolism is regulated by transcriptional and post-transcriptional mechanisms. The mRNA of the iron-controlling gene, transferrin receptor 1 (TfR1), has long been believed to be negatively regulated by a yet-unidentified endonuclease. Here, we show that the endonuclease Regnase-1 is critical for the degradation of mRNAs involved in iron metabolism in vivo. First, we demonstrate that Regnase-1 promotes TfR1 mRNA decay. Next, we show that Regnase-1−/− mice suffer from severe iron deficiency anemia, although hepcidin expression is downregulated. The iron deficiency anemia is induced by a defect in duodenal iron uptake. We reveal that duodenal Regnase-1 controls the expression of PHD3, which impairs duodenal iron uptake via HIF2α suppression. Finally, we show that Regnase-1 is a HIF2α-inducible gene and thus provides a positive feedback loop for HIF2α activation via PHD3. Collectively, these results demonstrate that Regnase-1-mediated regulation of iron-related transcripts is essential for the maintenance of iron homeostasis.
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•Regnase-1 destabilizes transferrin receptor 1 mRNAs via its ribonuclease activity•Lack of Regnase-1 leads to the development of severe iron deficiency anemia in vivo•Regnase-1 in the duodenal epithelium is required for iron homeostasis•Regnase-1 destabilizes PHD3 mRNA to facilitate duodenal iron uptake
Iron homeostasis is regulated by post-transcriptional mechanisms. Yoshinaga et al. demonstrate that an endoribonuclease, Regnase-1, destabilizes mRNAs related to iron metabolism, including TfR1 and PHD3. A positive feedback circuit of Regnase-1, PHD3, and HIF2α is critical for iron uptake in the duodenal epithelium and facilitates proper erythropoiesis.