RNF217 regulates iron homeostasis through its E3 ubiquitin ligase activity by modulating ferroportin degradation.
RNF217 regulates iron homeostasis through its E3 ubiquitin ligase activity by modulating ferroportin degradation.
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DOI：
10.1182/blood.2020008986
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发表时间：
2021-08-26
期刊：
影响因子：
20.3
通讯作者：
Wang F
中科院分区：
文献类型：
--
作者：
Jiang L;Wang J;Wang K;Wang H;Wu Q;Yang C;Yu Y;Ni P;Zhong Y;Song Z;Xie E;Hu R;Min J;Wang F
膜铁转运蛋白（FPN）是目前已知的唯一的细胞铁输出蛋白，在细胞内和全身铁稳态中起着重要作用，其水平受铁调素的调节。利用遗传筛选和模型，Jiang及其同事鉴定了一种E3泛素连接酶RNF 217，该酶促进FPN的降解，如果缺失，则以细胞类型依赖性方式干扰铁稳态。此外，他们确定了铁响应性脱甲基酶TET 1作为RNF 217的关键上游调节因子。这些数据进一步完善了我们对铁稳态的理解，以及如何操纵它。RNF 217作为一种新型的E3泛素连接酶，介导铁输出蛋白FPN的降解并调节铁稳态。Tet 1介导的去甲基化可上调Rnf 217的表达; Tet 1的缺失可稳定FPN并损害对铁过载的反应。转运铁蛋白（FPN）是人体唯一的铁输出蛋白，对维持全身铁稳态至关重要。响应于增加的铁或炎症，肝细胞分泌的铁调素结合FPN，诱导其内化和随后的降解。然而，作为FPN降解基础的E3泛素连接酶尚未鉴定。在这里，我们报告了一种新的机制，涉及RNF 217介导的降解FPN的鉴定和表征。2种不同E3筛选的组合揭示了Rnf 217基因是Tet 1的靶标，介导FPN的泛素化和随后的降解。有趣的是，Tet 1表达的缺失导致FPN的积累和对铁过载的反应受损，表现为肝脏中铁积累增加以及脾脏和十二指肠中铁减少。此外，我们发现，FPN的降解和泛素化可以通过突变RNF 217减弱。最后，使用2个条件性敲除小鼠品系，我们发现敲除巨噬细胞中的Rnf 217通过稳定FPN增加脾铁输出，而敲除肠细胞中的Rnf 217似乎增加铁吸收。这些发现表明Tet 1-RNF 217-FPN轴调节铁稳态，揭示了FPN相关疾病的新治疗靶点。
Ferroportin (FPN), the only known cellular iron exporter, plays a central role in intracellular and systemic iron homeostasis, and its levels are regulated by hepcidin. Using genetic screens and models, Jiang and colleagues identified an E3 ubiquitin ligase, RNF217, that promotes the degradation of FPN and that, if deleted, interferes with iron homeostasis in a cell type– dependent manner. Further, they identified the iron-responsive demethylase TET1 as a key upstream regulator of RNF217. These data further refine our understanding of iron homeostasis and how it can be manipulated. 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. 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.
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影响因子：
23.9
作者：
Dawlaty, Meelad M.;Ganz, Kibibi;Powell, Benjamin E.;Hu, Yueh-Chiang;Markoulaki, Styliani;Cheng, Albert W.;Gao, Qing;Kim, Jongpil;Choi, Sang-Woon;Page, David C.;Jaenisch, Rudolf
通讯作者：
Jaenisch, Rudolf
影响因子：
29
作者：
Drakesmith H;Nemeth E;Ganz T
通讯作者：
Ganz T
影响因子：
16.6
作者：
Choquet H;Paylakhi S;Kneeland SC;Thai KK;Hoffmann TJ;Yin J;Kvale MN;Banda Y;Tolman NG;Williams PA;Schaefer C;Melles RB;Risch N;John SWM;Nair KS;Jorgenson E
通讯作者：
Jorgenson E
影响因子：
29
作者：
Donovan, A;Lima, CA;Andrews, NC
通讯作者：
Andrews, NC
DOI：
10.1073/pnas.1323107111
发表时间：
2014-07-01
影响因子：
11.1
作者：
Ho, Shiuh-Rong;Mahanic, Christina S.;Lin, Weei-Chin
通讯作者：
Lin, Weei-Chin