Institute for Frontier Life and Medical Sciences, Kyoto University

Regnase-1 maintains iron homeostasis via the degradation of transferrin receptor 1 and prolyl hydroxylase domain-containing protein 3 mRNAs

Masanori Yoshinaga1,2, Yoshinari Nakatsuka1,2, Alexis Vandenbon3, Daisuke Ori1,6, Takuya Uehata1,2, Tohru Tsujimura4, Yutaka Suzuki5, Takashi Mino1,2, Osamu Takeuchi1,2

1Laboratory of Infection and Prevention, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University
2Agency for Medical Research and Development-Core Research for Evolutional Medical Science and Technology (AMED-CREST)
3Immuno-Genomics Research Unit, WPI Immunology Frontier Research Center (IFReC), Osaka University
4Department of Pathology, Hyogo College of Medicine
5Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo
6Laboratory of Molecular Immunobiology, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST)

Cell Reports 19 (2017) pp. 1614-1630. doi: 10.1016/j.celrep.2017.05.009

Abstract

Iron is required for essential biological functions including oxygen delivery, but iron overload has deleterious effects, as seen in an iron-related disorder, hemochromatosis. In order to circumvent iron deficiency or overload, iron metabolism is tightly controlled by multiple mechanisms including post-transcriptional regulations. The messenger RNA (mRNA) of the iron-controlling gene, transferrin receptor 1 (TfR1), has long been believed to be cleaved by a yet-unidentified endoribonuclease.
We have previously identified an endoribonuclease called Regnase-1 as an essential regulator of innate and adaptive immune system. Interestingly, we also found that mice which lack Regnase-1 also suffered from severe anemia as well as autoimmune disease. This finding motivated us to examine the role of Regnase-1 in iron metabolism.
In this study, we show that 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 investigate the role of Regnase-1 in vivo and show that Regnase-1–/– mice suffer from severe iron deficiency anemia. The anemia found under Regnase-1 deficiency was induced by a defect in duodenal iron uptake. We found that duodenal Regnase-1 controls the expression of PHD3, which impairs duodenal iron uptake via the suppression of a transcription factor HIF2α. Moreover, 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. This study will provide a novel insight into pathogenic mechanisms of anemia and iron-related disorders.
 

Figure 1. Model of Regnase-1-mediated regulation of duodenal iron uptake.