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

• DOI: 10.1016/j.celrep.2017.05.009
• Publication Date: 2017-05-23T18:01:15Z
• Authors: Masanori Yoshinaga; Yoshinari Nakatsuka; Alexis Vandenbon; Daisuke Ori; Takuya Uehata; Tohru Tsujimura; Yutaka Suzuki; Takashi Mino; Osamu Takeuchi
• Keywords: Transcription, Genetic; QH301-705.5; Duodenum; Iron; RNA Stability; Procollagen-Proline Dioxygenase; Response Elements; endonuclease; Mice; 03 medical and health sciences; Ribonucleases; Antigens, CD; Receptors, Transferrin; Basic Helix-Loop-Helix Transcription Factors; Animals; Homeostasis; iron metabolism; RNA, Messenger; Biology (General); Promoter Regions, Genetic; 0303 health sciences; Anemia; transferrin receptor; anemia; mRNA degradation; Ferritins; HIF2α

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.