||Regnase-1 Maintains Iron Homeostasis via the Degradation of Transferrin Receptor 1 and Prolyl-Hydroxylase-Domain-Containing Protein 3 mRNAs
Yoshinaga, Masanori ,
Nakatsuka, Yoshinari ,
Vandenbon, Alexis ,
Ori, Daisuke ,
Uehata, Takuya ,
Tsujimura, Tohru ,
Suzuki, Yutaka ,
Mino, TakashiTakeuchi, Osamu
1630 , 2017-05-23 , Elsevier BV
腸で鉄の吸収を調節するメカニズムの一端を解明 -- 貧血時に鉄吸収を促進するフィードバック機構を発見--. 京都大学プレスリリース. 2017-05-24.
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.