Identification of human genes of iron homeostasis

1)发育中的红细胞需要特别大量的铁，这些铁必须转移到线粒体，才能并入到血红素中。这种巨大的铁通量必须被精确控制，以允许血红素和血红蛋白的协调合成，同时避免化学活性铁的毒性影响。在培养的动物细胞中，铁伴侣Pcbp1和PCBP2将铁输送到铁蛋白，铁蛋白是细胞内唯一的铁储存蛋白，Ncoa4介导铁蛋白的自噬周转。PcBP、铁蛋白和Ncoa4在红系发育中的作用尚不清楚。在这里，我们展示了Pcbp1、Ncoa4和铁蛋白对小鼠红细胞发育至关重要。利用红系分化的培养细胞模型，Pcbp1或Ncoa4的缺失会损害通过铁蛋白的铁运输，从而导致血红素合成减少，血红蛋白形成减少，红系调节系统受到干扰。缺乏Pcbp1的小鼠表现出小细胞性贫血和通过调节促红细胞生成素和红细胞铁蛋白激活的代偿性红细胞生成。Pcbp1缺陷小鼠的红系前体细胞的体外分化证实了铁蛋白、铁通量和血红素合成方面的缺陷。这些研究证明了铁蛋白在进口铁向发育中的红细胞线粒体的矢量转移中的重要性，以及Pcbp1和Ncoa4在通过铁蛋白调节铁通量方面的重要性。 2)真核细胞含有数百种金属蛋白，这些金属蛋白由细胞内协调金属辅因子摄取和分布的系统支持。铁辅助因子包括血红素、铁硫簇和简单铁离子。Poly(RC)结合蛋白是一种多功能的适配器，作为胞液/核室中的铁离子伴侣，在输入时结合铁并将其运送到酶中，用于储存(铁蛋白)和出口(铁蛋白)。铁蛋白铁通过自噬通过货物受体、核共激活因子4被动员起来。单硫醇谷氧还蛋白Glrx3和BolA2以2Fe-2S伴侣复合体的形式发挥作用。这些蛋白质在哺乳动物细胞中形成了胞质铁辅助因子伴侣的核心系统。 3)一年中70%以上的铁 人类宿主在血液辅因子范围内 对携带氧气的蛋白质--血红蛋白 鲜血。铁是唯一的营养物质 通常会限制致病菌的生长 哺乳动物宿主中的微生物。 宿主通过多种途径对铁进行固存 是机构的内在组成部分 先天免疫反应。病原体有 进化出了许多策略来规避 寄主对铁的隔离；分泌物 一种血红素结合蛋白，称为 血团就是这样一种策略。在这 《自然微生物学》杂志，Nasser等人。 描述其结构和功能 一种分泌的血红素结合蛋白 白色念珠菌，揭示了独特的 霉菌悬浮液用于血液隔离 这种微生物遇到的问题。

1) Developing erythrocytes take up exceptionally large amounts of iron, which must be transferred to mitochondria for incorporation into heme. This massive iron flux must be precisely controlled to permit the coordinated synthesis of heme and hemoglobin while avoiding the toxic effects of chemically reactive iron. In cultured animal cells, iron chaperones Pcbp1 and Pcbp2 deliver iron to ferritin, the sole cytosolic iron storage protein, and Ncoa4 mediates the autophagic turnover of ferritin. The roles of Pcbp, ferritin, and Ncoa4 in erythroid development remain unclear. Here we show that Pcbp1, Ncoa4, and ferritin are critical for murine red cell development. Using a cultured cell model of erythroid differentiation, depletion of Pcbp1 or Ncoa4 impaired iron trafficking through ferritin, which resulted in reduced heme synthesis, reduced hemoglobin formation, and perturbation of erythroid regulatory systems. Mice lacking Pcbp1 exhibited microcytic anemia and activation of compensatory erythropoiesis via the regulators erythropoietin and erythroferrone. Ex vivo differentiation of erythroid precursors from Pcbp1-deficient mice confirmed defects in ferritin iron flux and heme synthesis. These studies demonstrate the importance of ferritin for the vectoral transfer of imported iron to mitochondria in developing red cells and of Pcbp1 and Ncoa4 in mediating iron flux through ferritin. 2) Eukaryotic cells contain hundreds of metalloproteins that are supported by intracellular systems coordinating the uptake and distribution of metal cofactors. Iron cofactors include heme, iron-sulfur clusters, and simple iron ions. Poly(rC)-binding proteins are multifunctional adaptors that serve as iron ion chaperones in the cytosolic/nuclear compartment, binding iron at import and delivering it to enzymes, for storage (ferritin), and export (ferroportin). Ferritin iron is mobilized by autophagy through the cargo receptor, nuclear co-activator 4. The monothiol glutaredoxin Glrx3 and BolA2 function as a 2Fe-2S chaperone complex. These proteins form a core system of cytosolic iron cofactor chaperones in mammalian cells. 3) Over 70% of the iron in a human host is in the haem cofactor bound to haemoglobin, the oxygen-carrying protein of blood. Iron is the single nutrient that typically limits the growth of pathogenic microorganisms in their mammalian hosts. Host sequestration of iron through a variety of mechanisms is an intrinsic part of the innate immune response. Pathogens have evolved numerous strategies to circumvent the iron sequestration of the host; secretion of haem-binding proteins, known as haemophores, is one such strategy. In this issue of Nature Microbiology, Nasser et al. characterize the structure and function of a secreted haem-binding protein of Candida albicans, and reveal the unique fungal solution to the haem-sequestration problem encountered by this microorganism.