Ferritin iron regulators, PCBP1 and NCOA4, respond to cellular iron status in developing red cells.
Ferritin iron regulators, PCBP1 and NCOA4, respond to cellular iron status in developing red cells.
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铁蛋白铁调节剂PCBP1和NCOA4对发育中的红细胞中的细胞铁状态反应。
DOI：
10.1016/j.bcmd.2017.09.009
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Philpott CC
中科院分区：
文献类型：
--
作者：
Ryu MS;Duck KA;Philpott CC
发育中的红细胞在终末分化过程中表现出多个冗余系统，用于调节和协调铁的摄取、血红素的合成和血红蛋白的形成。我们最近描述了多聚腺苷酸结合蛋白（PCBP 1）和核辅激活因子4（NCOA 4）在发育中的红系细胞中介导铁通过铁蛋白的通量中的作用，PCBP 1是一种铁伴侣，将铁传递到铁蛋白，NCOA 4是一种自噬货物受体，将铁蛋白引导到溶酶体进行降解和铁释放。铁蛋白铁通量是至关重要的，因为缺乏这些因子的小鼠会发生小细胞性贫血。在这里，我们报告说，这些过程是由细胞铁水平在离体终末分化的小鼠模型。PCBP 1通过直接的蛋白质-蛋白质相互作用将铁递送至铁蛋白。这种相互作用是发育调节，增强铁剥夺，抑制铁过量，无论是在发展中的细胞和体外。NCOA 4活性也表现出发育调节和细胞铁水平的调节。分化过程中过量的铁摄取触发了NCOA 4的溶酶体降解，这依赖于E3泛素连接酶HERC 2。因此，发育中的红细胞表达一系列蛋白质，这些蛋白质既介导又调节铁向线粒体的流动。
Developing red blood cells exhibit multiple, redundant systems for regulating and coordinating the uptake of iron, the synthesis of heme, and the formation of hemoglobin during terminal differentiation. We recently described the roles of poly rC-binding protein (PCBP1) and nuclear coactivator 4 (NCOA4) in mediating the flux of iron through ferritin in developing erythroid cells, with PCBP1, an iron chaperone, delivering iron to ferritin and NCOA4, an autophagic cargo receptor, directing ferritin to the lysosome for degradation and iron release. Ferritin iron flux is critical, as mice lacking these factors develop microcytic anemia. Here we report that these processes are regulated by cellular iron levels in a murine model of ex vivo terminal differentiation. PCBP1 delivers iron to ferritin via a direct protein-protein interaction. This interaction is developmentally regulated, enhanced by iron deprivation, and inhibited by iron excess, both in developing cells and in vitro. NCOA4 activity also exhibited developmental regulation and regulation by cellular iron levels. Excess iron uptake during differentiation triggered lysosomal degradation of NCOA4, which was dependent on the E3 ubiquitin ligase HERC2. Thus, developing red blood cells express a series of proteins that both mediate and regulate the flux of iron to the mitochondria.
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