Masanori Yoshinaga^1,2, Yoshinari Nakatsuka^1,2, Alexis Vandenbon³, Daisuke Ori^1,6, Takuya Uehata^1,2, Tohru Tsujimura⁴, Yutaka Suzuki⁵, Takashi Mino^1,2, Osamu Takeuchi^1,2

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

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.