title: The heme exporter Flvcr1 regulates expansion and differentiation of committed erythroid progenitors by controlling intracellular heme accumulation.
abstract: Feline leukemia virus subgroup C receptor 1 (Flvcr1) encodes two heme exporters: FLVCR1a, which localizes to the plasma membrane, and FLVCR1b, which 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 contributes to control the size of the 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 in Flvcr1a or Flvcr1b, respectively. Thus, heme export represents a tightly regulated process that controls erythropoiesis.
authors: Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Turin, Italy.
authors: Sonia
authors: S
authors: Mercurio
authors: Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Turin, Italy.
authors: Sara
authors: S
authors: Petrillo
authors: Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Turin, Italy.
authors: Deborah
authors: D
authors: Chiabrando
authors: Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Turin, Italy.
authors: Zuni Irma
authors: ZI
authors: Bassi
authors: Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Turin, Italy.
authors: Dafne
authors: D
authors: Gays
authors: Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Turin, Italy.
authors: Annalisa
authors: A
authors: Camporeale
authors: Tisch Cancer Institute and Black Family Stem Cell Institute, Division of Hematology and Medical Oncology and Departments of Developmental and Regenerative Biology and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Andrei
authors: A
authors: Vacaru
authors: Department of Veterinary Science, University of Turin, Italy.
authors: Barbara
authors: B
authors: Miniscalco
authors: Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Turin, Italy.
authors: Giulio
authors: G
authors: Valperga
authors: Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Turin, Italy.
authors: Lorenzo
authors: L
authors: Silengo
authors: Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Turin, Italy.
authors: Fiorella
authors: F
authors: Altruda
authors: Tisch Cancer Institute and Black Family Stem Cell Institute, Division of Hematology and Medical Oncology and Departments of Developmental and Regenerative Biology and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Margaret H
authors: MH
authors: Baron
authors: Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Turin, Italy Vesalius Research Center, VIB-KUL, Leuven, Belgium.
authors: Massimo Mattia
authors: MM
authors: Santoro
authors: Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Turin, Italy emanuela.tolosano@unito.it.
authors: Emanuela
authors: E
authors: Tolosano
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D004920:Erythropoiesis / Q000502:physiology*; D006418:Heme / Q000378:metabolism*; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism*; D020014:K562 Cells; D026901:Membrane Transport Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011991:Receptors, Virus / Q000502:physiology*; D015027:Zebrafish
chemical_list: C492690:FLVCR1 protein, human; D026901:Membrane Transport Proteins; D011991:Receptors, Virus; D006418:Heme