A cell-nonautonomous heme acquisition pathway enables erythroid hemoglobinization under stress

Cells have been thought to manage their own heme supply independently. However, over 1,000 proteins contribute to the production, transport, and regulation of the cofactor.

During terminal erythroid differentiation, cells lose their mitochondria yet continue to make hemoglobin, implying a non-canonical, cell-nonautonomous heme source. We show that under stress, erythroid precursors import heme through the permease Heme Responsive Gene 1 (HRG1), which localizes to the plasma membrane and accumulates during stress erythropoiesis, an accelerated production of red blood cells outside the bone marrow in response to anemia.