《生命科学》 2022, 34(7): 754-777

铁泵蛋白Ferroportin生理功能及其调控机制研究进展

李大航^1,2 , 徐　杉¹ , 蒋　丽¹ , 苏韵星¹ , 闵军霞^2,* , 王福俤^1,*

¹浙江大学医学院公共卫生学院/附属第四医院，杭州 310058 ²浙江大学医学院转化医学研究院，杭州 310058

摘　要：

铁泵蛋白(Ferroportin, FPN/SLC40A1) 是目前哺乳动物中唯一已知的铁外排膜蛋白，在调控机体铁稳态代谢过程中发挥重要作用。近年，围绕FPN 蛋白转运铁离子生理功能及其分子调控机制方面取得了令人瞩目的研究进展。FPN 蛋白通过从细胞内向外转运Fe²⁺ 参与许多关键生理过程，如细胞代谢、细胞命运以及铁死亡(ferroptosis) 等。铁调素(Hepcidin) 作为肝脏分泌的多肽，通过与FPN 蛋白结合导致FPN 内化降解，从而抑制小肠铁吸收及巨噬细胞的铁再循环，因此，Hepcidin-FPN 轴是机体系统性铁稳态调控的核心枢纽。然而，FPN 的具体降解机制一直是铁代谢领域内的热点及难点。近期，本研究团队发现E3 泛素连接酶RNF217 介导FPN 降解及其受TET1 ( 甲基胞嘧啶双加氧酶1) 修饰调控铁稳态代谢的新机制。临床研究发现，携带FPN 基因突变的个体出现不同临床表现的血色病。此外，有研究报道FPN 在肝脏疾病、肠道疾病、心脏疾病、贫血及癌症中发挥重要作用，提示FPN 或可成为防治这些疾病的关键靶点。本文系统综述了FPN 在金属离子转运、疾病发生及分子调控机制等方面的国内外最新研究进展，并就未来研究方向进行了展望和讨论。

通讯作者：闵军霞 , Email:junxiamin@zju.edu.cn 王福俤 , Email:fwang@zju.edu.cn

Physiological functions of iron exporter Ferroportin and its regulatory mechanism

LI Da-Hang^1,2 , XU Shan¹ , JIANG Li¹ , SU Yun-Xing¹ , MIN Jun-Xia^2,* , WANG Fu-Di^1,*

¹The Fourth Affiliated Hospital, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China ²Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China

Abstract:

Ferroportin (FPN, SLC40A1) is the membrane localized sole known iron exporter in mammals, which plays an important role for regulating iron homeostasis via exporting cellular ferrous iron. Recently, emerging studies suggest FPN possesses critical physiological functions, such as cell metabolism, cell fate and ferroptosis. In response to either iron or inflammation, liver-secreted Hepcidin binds to FPN for inducing its internalization and degradation. As a result, the Hepcidin-FPN axis serves as the master regulator of systemic iron homeostasis by mediating intestinal iron absorption and iron recycling in macrophages. However, the underlying mechanism of FPN degradation remains an unsolved enigma in the field. Until recently, we identified RNF217 as the E3 ubiquitin ligase to mediate FPN degradation, and it is regulated by the Tet1-RNF217-FPN axis for the maintenance of iron homeostasis. In clinic, FPN gene mutations cause hemochromatosis, an iron overload disease, with variable penetrance. Additionally, FPN has been linked to liver disease, intestinal disease, heart disease, anemia and cancer, suggesting its potential as a target for the prevention and treatment of these diseases. In this review, we summarize the progress of pathophysiological functions of FPN and current understanding of its regulatory mechanism. We also discuss our perspectives with regards to the future research direction.

Communication Author：MIN Jun-Xia , Email:junxiamin@zju.edu.cn WANG Fu-Di , Email:fwang@zju.edu.cn