i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal, Rua Alfredo Allen 208, 4200-135, Porto, Portugal.
IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal.
Sci Rep. 2017 Nov 1;7(1):14793. doi: 10.1038/s41598-017-14933-5.
Hepcidin is a small cysteine rich peptide that regulates the sole known cellular iron exporter, ferroportin, effectively controlling iron metabolism. Contrary to humans, where a single hepcidin exists, many fish have two functionally distinct hepcidin types, despite having a single ferroportin gene. This raises the question of whether ferroportin is similarly regulated by the iron regulator Hamp1 and the antimicrobial Hamp2. In sea bass (Dicentrarchus labrax), iron overload prompted a downregulation of ferroportin, associated with an upregulation of hamp1, whereas an opposite response was observed during anemia, with no changes in hamp2 in either situation. During infection, ferroportin expression decreased, indicating iron withholding to avoid microbial proliferation. In vivo administration of Hamp1 but not Hamp2 synthetic peptides caused significant reduction in ferroportin expression, indicating that in teleost fish with two hepcidin types, ferroportin activity is mediated through the iron-regulator Hamp1, and not through the dedicated antimicrobial Hamp2. Additionally, in vitro treatment of mouse macrophages with fish Hamp1 but not Hamp2 caused a decrease in ferroportin levels. These results raise questions on the evolution of hepcidin and ferroportin functional partnership and open new possibilities for the pharmaceutical use of selected fish Hamp2 hepcidins during infections, with no impact on iron homeostasis.
亚铁调素是一种富含半胱氨酸的小肽，可调节唯一已知的细胞铁输出蛋白——亚铁转运蛋白，从而有效控制铁代谢。与人类不同，人类只有一种亚铁调素，而许多鱼类有两种功能不同的亚铁调素类型，尽管它们只有一个亚铁转运蛋白基因。这就提出了一个问题，即铁调节蛋白 Hamp1 和抗菌蛋白 Hamp2 是否同样调节亚铁转运蛋白。在鲈鱼（Dicentrarchus labrax）中，铁过载会导致亚铁转运蛋白下调，同时 hamp1 上调，而在贫血时则出现相反的反应，两种情况下 hamp2 均无变化。在感染过程中，亚铁转运蛋白表达下降，表明铁的扣留以避免微生物增殖。体内给予 Hamp1 而不是 Hamp2 合成肽会导致亚铁转运蛋白表达显著减少，这表明在具有两种亚铁调素类型的硬骨鱼中，亚铁转运蛋白的活性是通过铁调节蛋白 Hamp1 介导的，而不是通过专门的抗菌蛋白 Hamp2 介导的。此外，体外用鱼 Hamp1 而非 Hamp2 处理小鼠巨噬细胞会导致亚铁转运蛋白水平降低。这些结果提出了关于亚铁调素和亚铁转运蛋白功能伙伴关系进化的问题，并为在感染期间使用选定的鱼 Hamp2 亚铁调素进行药物治疗开辟了新的可能性，而对铁稳态没有影响。
