Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA.
Cell Engineering Division, RIKEN BioResource Center, Tsukuba, Ibaraki, Japan.
J Exp Med. 2018 Feb 5;215(2):661-679. doi: 10.1084/jem.20170396. Epub 2017 Dec 27.
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.
铁限制型人类贫血与骨髓对造血细胞因子促红细胞生成素（Epo）产生抗性有关。铁含量的变化对 Epo 反应的调节是慢性病贫血静脉铁治疗的基础。Epo 与其受体结合通常可促进红系祖细胞的存活、增殖和分化。然而，铁限制引起的 Epo 抗性选择性地损害增殖和分化，同时保持细胞活力。我们的结果表明，铁限制限制了原代祖细胞中 Epo 受体的表面表达，而强制保留受体表面表达的小鼠在缺铁时不会发生贫血。研究发现了一种机制途径，即红系铁限制通过铁感应转铁蛋白受体 2 的介导下调受体控制元件 Scribble。Scribble 缺乏减少了 Epo 受体的表面表达，但通过 Akt 选择性地保留了存活信号。该机制将营养感应与受体功能整合在一起，使祖细胞扩增得以调节，而不会影响存活。
