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...

Full description

Bibliographic Details
Main Authors: Masanori Yoshinaga, Yoshinari Nakatsuka, Alexis Vandenbon, Daisuke Ori, Takuya Uehata, Tohru Tsujimura, Yutaka Suzuki, Takashi Mino, Osamu Takeuchi
Format: Article
Language:English
Published: Elsevier 2017-05-01
Series:Cell Reports
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124717306344
_version_ 1819014799612182528
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.
first_indexed 2024-12-21T02:21:35Z
format Article
id doaj.art-4478bd5cf27044d5a529b547ea52d3dc
institution Directory Open Access Journal
issn 2211-1247
language English
last_indexed 2024-12-21T02:21:35Z
publishDate 2017-05-01
publisher Elsevier
record_format Article
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
work_keys_str_mv AT masanoriyoshinaga regnase1maintainsironhomeostasisviathedegradationoftransferrinreceptor1andprolylhydroxylasedomaincontainingprotein3mrnas
AT yoshinarinakatsuka regnase1maintainsironhomeostasisviathedegradationoftransferrinreceptor1andprolylhydroxylasedomaincontainingprotein3mrnas
AT alexisvandenbon regnase1maintainsironhomeostasisviathedegradationoftransferrinreceptor1andprolylhydroxylasedomaincontainingprotein3mrnas
AT daisukeori regnase1maintainsironhomeostasisviathedegradationoftransferrinreceptor1andprolylhydroxylasedomaincontainingprotein3mrnas
AT takuyauehata regnase1maintainsironhomeostasisviathedegradationoftransferrinreceptor1andprolylhydroxylasedomaincontainingprotein3mrnas
AT tohrutsujimura regnase1maintainsironhomeostasisviathedegradationoftransferrinreceptor1andprolylhydroxylasedomaincontainingprotein3mrnas
AT yutakasuzuki regnase1maintainsironhomeostasisviathedegradationoftransferrinreceptor1andprolylhydroxylasedomaincontainingprotein3mrnas
AT takashimino regnase1maintainsironhomeostasisviathedegradationoftransferrinreceptor1andprolylhydroxylasedomaincontainingprotein3mrnas
AT osamutakeuchi regnase1maintainsironhomeostasisviathedegradationoftransferrinreceptor1andprolylhydroxylasedomaincontainingprotein3mrnas