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ZFIN ID: ZDB-PUB-150325-14
The Heme Exporter Flvcr1 Regulates Expansion And Differentiation Of Committed Erythroid Progenitors By Controlling Intracellular Heme Accumulation
Mercurio, S., Petrillo, S., Chiabrando, D., Bassi, Z.I., Gays, D., Camporeale, A., Vacaru, A., Miniscalco, B., Valperga, G., Silengo, L., Altruda, F., Baron, M.H., Santoro, M.M., Tolosano, E.
Date: 2015
Source: Haematologica   100(6): 720-9 (Journal)
Registered Authors: Gays, Dafne, Santoro, Massimo
Keywords: Bone Marrow Failure, Hematopoiesis, Red Cells, heme
MeSH Terms:
  • Amino Acid Sequence
  • Animals
  • Cell Differentiation/physiology*
  • Erythropoiesis/physiology*
  • Heme/metabolism*
  • Humans
  • Intracellular Fluid/metabolism*
  • K562 Cells
  • Membrane Transport Proteins/physiology*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Sequence Data
  • Receptors, Virus/physiology*
  • Zebrafish
PubMed: 25795718 Full text @ Haematologica
Feline Leukemia Virus subgroup C Receptor 1 (Flvcr1) encodes two heme exporters: Flvcr1a, that localizes to the plasma membrane, and Flvcr1b, that localizes to mitochondria. Here, we investigated the role of the two Flvcr1 isoforms during erythropoiesis. We showed that, in mice and zebrafish, Flvcr1a is required for the expansion of committed erythroid progenitors but cannot drive their terminal differentiation, while Flvcr1b contributes to the expansion phase and is required for differentiation. FLVCR1a-down-regulated K562 cells have defective proliferation, enhanced differentiation, and heme loading in the cytosol, while FLVCR1a/1b deficient K562 cells show impairment in both proliferation and differentiation, and accumulate heme in mitochondria. These data support a model in which the coordinated expression of Flvcr1a and Flvcr1b is contributes to control the size of cytosolic heme pool required to sustain metabolic activity during the expansion of erythroid progenitors and to allow hemoglobinization during their terminal maturation. Consistently, reduction or increase of the cytosolic heme rescued the erythroid defects in zebrafish deficient for Flvcr1a or Flvcr1b, respectively. Thus, heme export represents a tightly regulated process that controls erythropoiesis.