Erythroferrone inhibits the induction of hepcidin by BMP6
Erythroferrone inhibits the induction of hepcidin by BMP6
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DOI：
10.1182/blood-2018-06-857995
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发表时间：
2018-10-04
期刊：
影响因子：
20.3
通讯作者：
Drakesmithm, Hal
中科院分区：
文献类型：
--
作者：
Arezes, Joao;Foy, Niall;Drakesmithm, Hal
铁调素减少动员铁，促进红细胞生成，但过量的铁是β地中海贫血的致病因素。促红细胞生成素（EPO）通过成红细胞增强红铁酮（ERFE）的合成，而ERFE通过未知的机制抑制肝铁调素的产生。肝脏中的BMP/SMAD通路对于hepcidin控制是至关重要的，并且我们表明EPO以部分ERFE依赖的方式在体内抑制hepcidin和其他BMP靶基因。此外，重组ERFE抑制肝脏BMP/SMAD通路独立的血清和肝脏铁的变化。在体外，ERFE减少SMAD 1，SMADS和SMAD 8磷酸化，抑制BMP靶基因的表达。ERFE特异性地消除BMP 5、BMP 6和BMP 7对铁调素的诱导，但对BMP 2、BMP 4、BMP 9或激活素B对铁调素的诱导几乎没有影响。中和性抗ERFE抗体阻止ERFE抑制BMP 5、BMP 6和BMP 7对铁调素的诱导。无细胞均相时间分辨荧光分析表明，BMP 5，BMP 6和BMP 7竞争与ERFE的结合。我们的结论是，ERFE抑制hepcidin通过抑制肝BMP/SMAD信号通过优先损害一个进化密切相关的BMP亚组的BMP 5，BMP 6和BMP 7。ERFE可以作为一个天然的配体陷阱产生的刺激红细胞生成，以调节铁的可用性。
Decreased hepcidin mobilizes iron, which facilitates erythropoiesis, but excess iron is pathogenic in beta-thalassemia. Erythropoietin (EPO) enhances erythroferrone (ERFE) synthesis by erythroblasts, and ERFE suppresses hepatic hepcidin production through an unknown mechanism. The BMP/SMAD pathway in the liver is critical for hepcidin control, and we show that EPO suppressed hepcidin and other BMP target genes in vivo in a partially ERFE-dependent manner. Furthermore, recombinant ERFE suppressed the hepatic BMP/SMAD pathway independently of changes in serum and liver iron. In vitro, ERFE decreased SMAD1, SMADS, and SMAD8 phosphorylation and inhibited expression of BMP target genes. ERFE specifically abrogated the induction of hepcidin by BMP5, BMP6, and BMP7 but had little or no effect on hepcidin induction by BMP2, BMP4, BMP9, or activin B. A neutralizing anti-ERFE antibody prevented ERFE from inhibiting hepcidin induction by BMP5, BMP6, and BMP7. Cell-free homogeneous time-resolved fluorescence assays showed that BMP5, BMP6, and BMP7 competed with anti-ERFE for binding to ERFE. We conclude that ERFE suppresses hepcidin by inhibiting hepatic BMP/SMAD signaling via preferentially impairing an evolutionarily closely related BMP subgroup of BMP5, BMP6, and BMP7. ERFE can act as a natural ligand trap generated by stimulated erythropoiesis to regulate the availability of iron.