Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Cell Metab. 2012 Jun 6;15(6):918-24. doi: 10.1016/j.cmet.2012.03.018.
Ferroportin exports iron into plasma from absorptive enterocytes, erythrophagocytosing macrophages, and hepatic stores. The hormone hepcidin controls cellular iron export and plasma iron concentrations by binding to ferroportin and causing its internalization and degradation. We explored the mechanism of hepcidin-induced endocytosis of ferroportin, the key molecular event in systemic iron homeostasis. Hepcidin binding caused rapid ubiquitination of ferroportin in cell lines overexpressing ferroportin and in murine bone marrow-derived macrophages. No hepcidin-dependent ubiquitination was observed in C326S ferroportin mutant which does not bind hepcidin. Substitutions of lysines between residues 229 and 269 in the third cytoplasmic loop of ferroportin prevented hepcidin-dependent ubiquitination and endocytosis of ferroportin, and promoted cellular iron export even in the presence of hepcidin. The human ferroportin mutation K240E, previously associated with clinical iron overload, caused hepcidin resistance in vitro by interfering with ferroportin ubiquitination. Our study demonstrates that ubiquitination is the functionally relevant signal for hepcidin-induced ferroportin endocytosis.
铁蛋白将铁从吸收肠细胞、噬红细胞巨噬细胞和肝储存中输出到血浆中。激素铁调素通过与铁蛋白结合并导致其内化和降解来控制细胞铁输出和血浆铁浓度。我们探讨了铁调素诱导铁蛋白内吞的机制，这是全身铁稳态的关键分子事件。在过表达铁蛋白的细胞系和鼠骨髓来源的巨噬细胞中，铁调素结合导致铁蛋白的快速泛素化。在不结合铁调素的 C326S 铁蛋白突变体中未观察到铁调素依赖性泛素化。铁蛋白第三胞质环中残基 229 至 269 之间赖氨酸的取代可防止铁调素依赖性铁蛋白泛素化和内吞作用，并促进细胞铁输出，即使存在铁调素也是如此。先前与临床铁过载相关的人类铁蛋白突变 K240E 通过干扰铁蛋白泛素化在体外引起铁调素抵抗。我们的研究表明，泛素化是铁调素诱导铁蛋白内吞的功能相关信号。
