A Heme Export Protein Is Required for Red Blood Cell Differentiation and Iron Homeostasis

TLDR

Hemoproteins are essential for aerobic cell function, but free heme is toxic, requiring cells to tightly regulate synthesis and utilization. Loss of FLVCR in mice disrupts erythropoiesis, causes craniofacial and limb defects, and leads to midgestation death, while neonatal deletion produces macrocytic anemia and maturation arrest, demonstrating that FLVCR‑mediated heme export from erythroid precursors and macrophages is essential for erythropoiesis and systemic iron homeostasis.

Abstract

Hemoproteins are critical for the function and integrity of aerobic cells. However, free heme is toxic. Therefore, cells must balance heme synthesis with its use. We previously demonstrated that the feline leukemia virus, subgroup C, receptor (FLVCR) exports cytoplasmic heme. Here, we show that FLVCR-null mice lack definitive erythropoiesis, have craniofacial and limb deformities resembling those of patients with Diamond-Blackfan anemia, and die in midgestation. Mice with FLVCR that is deleted neonatally develop a severe macrocytic anemia with proerythroblast maturation arrest, which suggests that erythroid precursors export excess heme to ensure survival. We further demonstrate that FLVCR mediates heme export from macrophages that ingest senescent red cells and regulates hepatic iron. Thus, the trafficking of heme, and not just elemental iron, facilitates erythropoiesis and systemic iron balance.