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.
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