Regnase-1 Maintains Iron Homeostasis via the Degradation of Transferrin Receptor 1 and Prolyl-Hydroxylase-Domain-Containing Protein 3 mRNAs
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 f...
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Elsevier
2017-05-01
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Series: | Cell Reports |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717306344 |
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author | Masanori Yoshinaga Yoshinari Nakatsuka Alexis Vandenbon Daisuke Ori Takuya Uehata Tohru Tsujimura Yutaka Suzuki Takashi Mino Osamu Takeuchi |
author_facet | Masanori Yoshinaga Yoshinari Nakatsuka Alexis Vandenbon Daisuke Ori Takuya Uehata Tohru Tsujimura Yutaka Suzuki Takashi Mino Osamu Takeuchi |
author_sort | Masanori Yoshinaga |
collection | DOAJ |
description | 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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institution | Directory Open Access Journal |
issn | 2211-1247 |
language | English |
last_indexed | 2024-12-21T02:21:35Z |
publishDate | 2017-05-01 |
publisher | Elsevier |
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series | Cell Reports |
spelling | doaj.art-4478bd5cf27044d5a529b547ea52d3dc2022-12-21T19:19:08ZengElsevierCell Reports2211-12472017-05-011981614163010.1016/j.celrep.2017.05.009Regnase-1 Maintains Iron Homeostasis via the Degradation of Transferrin Receptor 1 and Prolyl-Hydroxylase-Domain-Containing Protein 3 mRNAsMasanori Yoshinaga0Yoshinari Nakatsuka1Alexis Vandenbon2Daisuke Ori3Takuya Uehata4Tohru Tsujimura5Yutaka Suzuki6Takashi Mino7Osamu Takeuchi8Laboratory of Infection and Prevention, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, JapanLaboratory of Infection and Prevention, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, JapanImmuno-Genomics Research Unit, WPI Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, JapanLaboratory of Infection and Prevention, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, JapanLaboratory of Infection and Prevention, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, JapanDepartment of Pathology, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, JapanLaboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa-shi, Chiba 277-8562, JapanLaboratory of Infection and Prevention, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, JapanLaboratory of Infection and Prevention, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, JapanIron 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.http://www.sciencedirect.com/science/article/pii/S2211124717306344iron metabolismmRNA degradationanemiaHIF2αtransferrin receptorendonuclease |
spellingShingle | Masanori Yoshinaga Yoshinari Nakatsuka Alexis Vandenbon Daisuke Ori Takuya Uehata Tohru Tsujimura Yutaka Suzuki Takashi Mino Osamu Takeuchi Regnase-1 Maintains Iron Homeostasis via the Degradation of Transferrin Receptor 1 and Prolyl-Hydroxylase-Domain-Containing Protein 3 mRNAs Cell Reports iron metabolism mRNA degradation anemia HIF2α transferrin receptor endonuclease |
title | Regnase-1 Maintains Iron Homeostasis via the Degradation of Transferrin Receptor 1 and Prolyl-Hydroxylase-Domain-Containing Protein 3 mRNAs |
title_full | Regnase-1 Maintains Iron Homeostasis via the Degradation of Transferrin Receptor 1 and Prolyl-Hydroxylase-Domain-Containing Protein 3 mRNAs |
title_fullStr | Regnase-1 Maintains Iron Homeostasis via the Degradation of Transferrin Receptor 1 and Prolyl-Hydroxylase-Domain-Containing Protein 3 mRNAs |
title_full_unstemmed | Regnase-1 Maintains Iron Homeostasis via the Degradation of Transferrin Receptor 1 and Prolyl-Hydroxylase-Domain-Containing Protein 3 mRNAs |
title_short | Regnase-1 Maintains Iron Homeostasis via the Degradation of Transferrin Receptor 1 and Prolyl-Hydroxylase-Domain-Containing Protein 3 mRNAs |
title_sort | regnase 1 maintains iron homeostasis via the degradation of transferrin receptor 1 and prolyl hydroxylase domain containing protein 3 mrnas |
topic | iron metabolism mRNA degradation anemia HIF2α transferrin receptor endonuclease |
url | http://www.sciencedirect.com/science/article/pii/S2211124717306344 |
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