RNF217 regulates iron homeostasis through its E3 ubiquitin ligase activity by modulating ferroportin degradation

• Published in: Blood Vol. 138; no. 8; pp. 689 - 705
• Main Authors: Jiang, Li, Wang, Jiaming, Wang, Kai, Wang, Hao, Wu, Qian, Yang, Cong, Yu, Yingying, Ni, Pu, Zhong, Yueyang, Song, Zijun, Xie, Enjun, Hu, Ronggui, Min, Junxia, Wang, Fudi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.08.2021; American Society of Hematology
• Subjects: Animals; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Iron - metabolism; Iron Overload - genetics; Iron Overload - metabolism; Mice; Mice, Knockout; Organ Specificity - genetics; Proteolysis; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Red Cells, Iron, and Erythropoiesis; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2020008986

Ferroportin (FPN), the body's sole iron exporter, is essential for maintaining systemic iron homeostasis. In response to either increased iron or inflammation, hepatocyte-secreted hepcidin binds to FPN, inducing its internalization and subsequent degradation. However, the E3 ubiquitin ligase that underlies FPN degradation has not been identified. Here, we report the identification and characterization of a novel mechanism involving the RNF217-mediated degradation of FPN. A combination of 2 different E3 screens revealed that the Rnf217 gene is a target of Tet1, mediating the ubiquitination and subsequent degradation of FPN. Interestingly, loss of Tet1 expression causes an accumulation of FPN and an impaired response to iron overload, manifested by increased iron accumulation in the liver together with decreased iron in the spleen and duodenum. Moreover, we found that the degradation and ubiquitination of FPN could be attenuated by mutating RNF217. Finally, using 2 conditional knockout mouse lines, we found that knocking out Rnf217 in macrophages increases splenic iron export by stabilizing FPN, whereas knocking out Rnf217 in intestinal cells appears to increase iron absorption. These findings suggest that the Tet1-RNF217-FPN axis regulates iron homeostasis, revealing new therapeutic targets for FPN-related diseases. •RNF217 functions as a novel E3 ubiquitin ligase, mediating the degradation of the iron exporter FPN and regulating iron homeostasis.•Rnf217 expression is upregulated by Tet1-mediated demethylation; loss of Tet1 stabilizes FPN and impairs the response to iron overload. [Display omitted]