Iron-restricted human anemias are associated with the acquisition of marrow resistance to the hematopoietic cytokine erythropoietin (Epo). Regulation of Epo responsiveness by iron availability serves as the basis for intravenous iron therapy in anemias of chronic disease. Epo engagement of its receptor normally promotes survival, proliferation, and differentiation of erythroid progenitors. However, Epo resistance caused by iron restriction selectively impairs proliferation and differentiation while preserving viability. Our results reveal that iron restriction limits surface display of Epo receptor in primary progenitors and that mice with enforced surface retention of the receptor fail to develop anemia with iron deprivation. A mechanistic pathway is identified in which erythroid iron restriction down-regulates a receptor control element, Scribble, through the mediation of the iron-sensing transferrin receptor 2. Scribble deficiency reduces surface expression of Epo receptor but selectively retains survival signaling via Akt. This mechanism integrates nutrient sensing with receptor function to permit modulation of progenitor expansion without compromising survival.

铁限制的人类贫血与骨髓对造血细胞因子促红细胞生成素（Epo）的抵抗力的获得有关。铁的可利用性对Epo反应性的调节是慢性疾病性贫血中静脉铁剂治疗的基础。Epo与其受体的结合通常可促进红系祖细胞的存活，增殖和分化。但是，铁限制引起的Epo抗性选择性地损害了增殖和分化，同时保留了活力。我们的研究结果表明，铁的限制限制了Epo受体在原代祖细胞中的表面展示，并且具有增强的受体表面保留作用的小鼠未能因缺铁而发展为贫血。确定了一种机制途径，其中红系铁的限制下调了受体控制元件，通过铁感性转铁蛋白受体2的介导进行涂抹。涂抹不足会降低Epo受体的表面表达，但会通过Akt选择性保留存活信号。该机制将营养感测与受体功能整合在一起，从而可以调节祖细胞的扩增而不会影响生存。