Identification of human genes of iron homeostasis

1)发育中的红细胞会摄取大量的铁，这些铁必须被转移到线粒体中以结合到血红素中。必须精确控制这种大量的铁流量，以允许血红素和血红蛋白的协调合成，同时避免化学反应性铁的毒性作用。在培养的动物细胞中，铁分子伴侣Pcbp 1和Pcbp 2将铁传递给铁蛋白，铁蛋白是唯一的胞质铁储存蛋白，Ncoa 4介导铁蛋白的自噬周转。Pcbp、铁蛋白和Ncoa 4在红系发育中的作用尚不清楚。在这里，我们表明，Pcbp 1，Ncoa 4和铁蛋白是小鼠红细胞发育的关键。使用培养的红系分化细胞模型，Pcbp 1或Ncoa 4的耗竭损害通过铁蛋白的铁运输，这导致血红素合成减少，血红蛋白形成减少，和红系调节系统的扰动。缺乏Pcbp 1的小鼠表现出小红细胞性贫血，并通过调节促红细胞生成素和红细胞铁酮激活代偿性红细胞生成。Pcbp 1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的缺陷。这些研究表明，铁蛋白的重要性，进口的铁在发展中的红细胞和Pcbp 1和Ncoa 4介导的铁通量通过铁蛋白的线粒体的矢量转移。 2)真核细胞含有数百种金属蛋白，这些金属蛋白由细胞内系统支持，协调金属辅因子的摄取和分布。铁辅因子包括血红素、铁硫簇和简单铁离子。聚（rC）结合蛋白是多功能衔接子，其在胞质/核隔室中充当铁离子伴侣，在输入时结合铁并将其递送至酶，用于储存（铁蛋白）和输出（膜铁转运蛋白）。铁蛋白铁通过自噬通过货物受体，核共激活因子4动员。单硫醇谷氧还蛋白Glrx 3和BolA 2作为2Fe-2S伴侣复合物发挥功能。这些蛋白质在哺乳动物细胞中形成胞质铁辅因子分子伴侣的核心系统。 3)超过70%的铁元素 人类宿主处于血红素辅因子结合中 到血红蛋白，这种携氧蛋白 鲜血铁是唯一的营养素， 通常限制了致病性 微生物在其哺乳动物宿主中。 通过多种方式对铁进行宿主螯合 的机制是一个内在的一部分， 先天免疫反应病原体 进化出了许多策略来规避 宿主的铁螯合;分泌 血红素结合蛋白， 血细胞，就是这样一种策略。在这 《自然微生物学》杂志，Nasser等人， 结构与功能表征 分泌的血红素结合蛋白 白色念珠菌，并揭示了独特的 真菌解决血液隔离 这是微生物遇到的问题。

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.