Bayele Henry K, Srai Surjit Kaila S
Department of Structural & Molecular Biology, University College London, Darwin Building, Gower Street, London, WC1E 6BT, United Kingdom.
Biochem Biophys Rep. 2021 Jan 8;25:100873. doi: 10.1016/j.bbrep.2020.100873. eCollection 2021 Mar.
Ferroportin (Fpn/IREG1/MTP1) is the only known transporter mediating iron efflux from epithelial cells and macrophages, and thus regulates how much iron is released into the circulation. Consequently, Fpn mutations are associated with haemochromatosis. Fpn itself is post-translationally regulated by hepcidin (Hepc) which induces its redistribution and degradation in a ubiquitin-dependent process. Together, the two proteins appear to be the nexus for iron homeostasis. Here we show that a rare gain-of-function mutation (K240E) that is associated with iron overload, impedes Fpn binding and subcellular trafficking by the small ubiquitin-like modifier (SUMO). Whereas wild-type Fpn is ensconced within vesicular bodies, the FpnK240E mutant appeared diffused within the cell when co-expressed with SUMO. Furthermore, compared with wild type Fpn, the sumoylation-defective mutant was constitutively-active, resulting in a lower intracellular labile iron pool than the former. These findings suggest that SUMO may regulate iron homeostasis by controlling Fpn trafficking.
铁转运蛋白（Fpn/IREG1/MTP1）是目前已知的唯一介导上皮细胞和巨噬细胞铁外流的转运蛋白，因此它调控着释放到循环系统中的铁量。因此，Fpn突变与血色素沉着症相关。Fpn自身在翻译后受铁调素（Hepc）调控，铁调素在泛素依赖的过程中诱导其重新分布和降解。这两种蛋白共同构成了铁稳态的关键环节。我们在此表明，一种与铁过载相关的罕见功能获得性突变（K240E），会阻碍小泛素样修饰物（SUMO）与Fpn的结合及其亚细胞转运。野生型Fpn定位于囊泡小体中，而FpnK240E突变体与SUMO共表达时则在细胞内呈弥散状态。此外，与野生型Fpn相比，SUMO化缺陷型突变体具有组成型活性，导致细胞内不稳定铁池比野生型更低。这些发现表明，SUMO可能通过控制Fpn的转运来调节铁稳态。
