Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon 97239.
Department of Pediatrics, Oregon Health and Science University, Portland, Oregon 97239.
J Biol Chem. 2020 Mar 20;295(12):3906-3917. doi: 10.1074/jbc.RA119.010535. Epub 2020 Feb 13.
Transferrin receptor 2 (TFR2) is a transmembrane protein expressed mainly in hepatocytes and in developing erythroid cells and is an important focal point in systemic iron regulation. Loss of TFR2 function results in a rare form of the iron-overload disease hereditary hemochromatosis. Although TFR2 in the liver has been shown to be important for regulating iron homeostasis in the body, TFR2's function in erythroid progenitors remains controversial. In this report, we analyzed TFR2-deficient mice in the presence or absence of iron overload to distinguish between the effects caused by a high iron load and those caused by loss of TFR2 function. Analysis of bone marrow from TFR2-deficient mice revealed a reduction in the early burst-forming unit-erythroid and an expansion of late-stage erythroblasts that was independent of iron overload. Spleens of TFR2-deficient mice displayed an increase in colony-forming unit-erythroid progenitors and in all erythroblast populations regardless of iron overload. This expansion of the erythroid compartment coincided with increased erythroferrone (ERFE) expression and serum erythropoietin (EPO) levels. Rescue of hepatic TFR2 expression normalized hepcidin expression and the total cell count of the bone marrow and spleen, but it had no effect on erythroid progenitor frequency. On the basis of these results, we propose a model of TFR2's function in murine erythropoiesis, indicating that deficiency in this receptor is associated with increased erythroid development and expression of EPO and ERFE in extrahepatic tissues independent of TFR's role in the liver.
转铁蛋白受体 2（TFR2）是一种主要在肝细胞和正在发育的红细胞中表达的跨膜蛋白，是全身铁调节的重要焦点。TFR2 功能丧失会导致一种罕见的铁过载疾病遗传性血色素沉着症。尽管肝脏中的 TFR2 已被证明对调节体内铁平衡很重要，但 TFR2 在红细胞祖细胞中的功能仍存在争议。在本报告中，我们分析了存在或不存在铁过载的 TFR2 缺陷小鼠，以区分由高铁负荷引起的影响和由 TFR2 功能丧失引起的影响。对 TFR2 缺陷小鼠骨髓的分析显示，早期爆式集落形成单位-红细胞减少，晚期红细胞增多，这与铁过载无关。TFR2 缺陷小鼠的脾脏显示无论是否存在铁过载，集落形成单位-红细胞祖细胞和所有红细胞群体均增加。这种红细胞区室的扩张伴随着红细胞生成素（ERFE）表达和血清促红细胞生成素（EPO）水平的增加。肝 TFR2 表达的恢复使亚铁调素表达和骨髓和脾脏的总细胞计数正常化，但对红细胞祖细胞频率没有影响。基于这些结果，我们提出了 TFR2 在小鼠红细胞生成中的功能模型，表明该受体的缺乏与 EPO 和 ERFE 在肝外组织中的红细胞发育和表达增加有关，而与 TFR 在肝脏中的作用无关。
