Model of iron regulation in replete and restricted erythropoiesis. (A) In the iron-replete condition, small amounts of Epo induce proliferation and differentiation of erythroblasts that take up iron by binding diferric transferrin at TfR1 for Hb synthesis. During iron deficiency, circulating transferrin is either devoid of iron (apotransferrin) or bound to iron at only 1 binding site (monoferric transferrin) with a significantly decreased concentration of diferric transferrin. Thus, in addition to less iron uptake owing to a decrease in diferric transferrin and resulting in a decrease in Hb synthesis per cell, iron restriction decreases Epo responsiveness, modifying Epo receptor–dependent signaling to support cell viability in excess of erythroid proliferation and differentiation. (B) In iron-replete conditions, diferric Tf binding to TfR2 prevents trafficking of TfR2-associated vesicles to lysosomes, enabling “free” SCRIBBLE to promote efficient EpoR surface presentation and normal Epo responsiveness. In iron-deficient conditions, TfR2-associated vesicles traffic predominantly to lysosomes, accelerating catabolism of TfR2-Scribble complexes and resulting in impaired Scribble-mediated EpoR delivery to the cell surface. Because SCRIBBLE suppresses AKT signaling, STAT5-dependent signal predominates in iron-replete conditions, supporting erythroid differentiation. In contrast, trafficking of Scribble to the lysosome in iron-deficient conditions results in persistent AKT signaling, impeding erythroid differentiation. (C) Nuclear receptor coactivator 4 (NCOA4) is a selective cargo receptor for autophagic ferritin turnover, critical for regulation of intracellular iron availability. In iron-replete states, NCOA4 binds iron, undergoes ubiquitination, and is targeted to the proteasome for degradation. In iron-deficient conditions, NCOA4 is stabilized and participates in trafficking ferritin to the lysosome, enabling iron release from ferritin and transport to the mitochondria for heme synthesis. This orchestration of erythropoiesis in parallel with iron availability prevents the proliferation and differentiation of erythroblasts when there is insufficient iron to support commensurate Hb synthesis and protects from replication stress in the absence of adequate iron. The mechanisms involved are beginning to come to light. AKT, protein kinase B; EPO, erythropoietin; EpoR, erythropoietin receptor; Fe, iron; NCOA4, nuclear receptor coactivator 4; RBC, red blood cell; STAT, signal transducer and activator of transcription; Tf, transferrin; TfR, transferrin receptor.