PCBP1 and NCOA4 regulate erythroid iron storage and heme biosynthesis

J Clin Invest. 2017 May 1;127(5):1786-1797. doi: 10.1172/JCI90519. Epub 2017 Apr 4.


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 poly rC-binding protein 1 (PCBP1) and PCBP2 deliver iron to ferritin, the sole cytosolic iron storage protein, and nuclear receptor coactivator 4 (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 vectorial transfer of imported iron to mitochondria in developing red cells and of PCBP1 and NCOA4 in mediating iron flux through ferritin.

MeSH terms

  • Anemia / genetics
  • Anemia / metabolism
  • Animals
  • Biological Transport, Active / genetics
  • CHO Cells
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cricetinae
  • Cricetulus
  • Cytokines / genetics
  • Cytokines / metabolism
  • DNA-Binding Proteins
  • Erythrocytes / metabolism*
  • Erythropoietin / genetics
  • Erythropoietin / metabolism
  • Ferritins / genetics
  • Ferritins / metabolism
  • Heme / biosynthesis*
  • Heme / genetics
  • Humans
  • Iron / metabolism*
  • Mice
  • Mice, Transgenic
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Nuclear Receptor Coactivators / genetics
  • Nuclear Receptor Coactivators / metabolism*
  • RNA-Binding Proteins


  • Carrier Proteins
  • Cytokines
  • DNA-Binding Proteins
  • Erfe protein, mouse
  • Muscle Proteins
  • NcoA4 protein, mouse
  • Nuclear Receptor Coactivators
  • Pcbp1 protein, mouse
  • RNA-Binding Proteins
  • Erythropoietin
  • Heme
  • Ferritins
  • Iron