Heme-regulated eIF2α kinase (HRI) is required for translational regulation and survival of erythroid precursors in iron deficiency
Heme-regulated eIF2α kinase (HRI) is required for translational regulation and survival of erythroid precursors in iron deficiency
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DOI：
10.1093/emboj/20.23.6909
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发表时间：
2001-12-03
期刊：
影响因子：
11.4
通讯作者：
Chen, JJ
中科院分区：
文献类型：
--
作者：
Han, AP;Yu, C;Chen, JJ
虽然在生物化学研究的基础上，长期以来一直怀疑哺乳动物中基因表达的组织特异性翻译控制的生理作用，但一直缺乏直接证据。在这里，我们报告了对小鼠中编码血红素调节的eIF 2 α激酶（HRI）的基因的靶向破坏。我们确定，HRI，这是主要在红细胞系细胞中表达，调节合成的α-和β-球蛋白在红细胞（RBC）前体抑制一般翻译起始因子eIF 2。当血红素的细胞内浓度下降时，这种抑制作用就会发生，从而阻止血红素过量的珠蛋白肽的合成。在缺铁的HRI-/-小鼠中，缺乏血红素的球蛋白在RBC及其前体中聚集，导致红细胞计数减少、红细胞代偿性增生以及骨髓和脾脏中细胞凋亡加速的高色素性、正常红细胞性贫血。因此，HRI是红系细胞系中基因表达和细胞存活的生理调节剂。
Although the physiological role of tissue-specific translational control of gene expression in mammals has long been suspected on the basis of biochemical studies, direct evidence has been lacking. Here, we report on the targeted disruption of the gene encoding the heme-regulated eIF2 alpha kinase (HRI) in mice. We establish that HRI, which is expressed predominantly in erythroid cells, regulates the synthesis of both alpha -and beta -globins in red blood cell (RBC) precursors by inhibiting the general translation initiation factor eIF2. This inhibition occurs when the intracellular concentration of heme declines, thereby preventing the synthesis of globin peptides in excess of heme. In iron-deficient HRI-/- mice, globins devoid of heme aggregated within the RBC and its precursors, resulting in a hyperchromic, normocytic anemia with decreased RBC counts, compensatory erythroid hyperplasia and accelerated apoptosis in bone marrow and spleen. Thus, HRI is a physiological regulator of gene expression and cell survival in the erythroid lineage.