期刊
CELL REPORTS
卷 19, 期 8, 页码 1614-1630出版社
CELL PRESS
DOI: 10.1016/j.celrep.2017.05.009
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资金
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [221S0002, 16H06279]
- Japan Society for the Promotion of Science (JSPS)
- Takeda Science Foundation
- Uehara Memorial Foundation
- Grants-in-Aid for Scientific Research [16J08040, 16H06279, 17K15726, 16H06898, 16K08832] Funding Source: KAKEN
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 HIF2 alpha suppression. Finally, we show that Regnase-1 is a HIF2 alpha-inducible gene and thus provides a positive feedback loop for HIF2 alpha 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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