Translational control by heme-regulated elF2α kinase during erythropoiesis.
Translational control by heme-regulated elF2α kinase during erythropoiesis.
复制标题
红血管调节的ELF2α激酶在红细胞生成过程中受到翻译控制。
DOI：
10.1097/moh.0000000000000704
复制
发表时间：
2022-05-01
影响因子：
3.2
通讯作者：
Zhang, Shuping
中科院分区：
文献类型：
--
作者：
Chen, Jane-Jane;Zhang, Shuping
关键词：
HRI是血红素调节的eIF 2 α激酶，可磷酸化eIF 2的α亚基。虽然HRI在抑制红系细胞中珠蛋白合成中的作用已被充分确立，但最近已发现HRI在翻译中的更广泛作用。本文就HRI在应激性红细胞生成和胎儿γ-珠蛋白表达中的新发现作一综述。HRI和ATF 4 mRNA在早期成红细胞中高度表达。HRI-eIF 2 αP抑制蛋白质合成是维持细胞质和线粒体中蛋白质稳态所必需的。此外，HRI-eIF 2 αP特异性增强ATF 4 mRNA的翻译，导致mTORC 1信号转导的抑制。ATF 4靶基因在铁缺乏期间最高度活化，以维持线粒体功能、氧化还原稳态，并使红细胞分化成为可能。因此，HRI是红细胞生成的主要翻译调节剂，其感测细胞内血红素浓度和氧化应激以实现有效的红细胞生成。有趣的是，HRI-eIF 2 α P-ATF 4信号传导也抑制人红系细胞中胎儿血红蛋白的产生。HRI的主要功能是维持蛋白质稳态，同时诱导ATF 4以减轻应激。HRI-ATF 4在γ-珠蛋白表达中的作用提高了HRI作为血红蛋白病治疗靶点的潜力。
HRI is the heme-regulated eIF2αkinase that phosphorylates the α-subunit of eIF2. While the role of HRI in inhibiting globin synthesis in erythroid cells is well established, broader roles of HRI in translation have been uncovered recently. This review is to summarize the new discoveries of HRI in stress erythropoiesis and in fetal γ-globin expression. HRI and ATF4 mRNAs are highly expressed in early erythroblasts. Inhibition of protein synthesis by HRI-eIF2αP is necessary to maintain protein homeostasis in both the cytoplasm and mitochondria. Additionally, HRI-eIF2αP specifically enhances translation of ATF4 mRNA leading to the repression of mTORC1 signaling. ATF4 target genes are most highly activated during iron deficiency to maintain mitochondrial function, redox homeostasis, and to enable erythroid differentiation. HRI is therefore a master translation regulator of erythropoiesis sensing intracellular heme concentrations and oxidative stress for effective erythropoiesis. Intriguingly, HRI-eIF2αP-ATF4 signaling also inhibits fetal hemoglobin production in human erythroid cells. The primary function of HRI is to maintain protein homeostasis accompanied by the induction of ATF4 to mitigate stress. Role of HRI-ATF4 in γ-globin expression raises the potential of HRI as a therapeutic target for hemoglobinopathy.
影响因子：
8.8
作者：
Yan X;Himburg HA;Pohl K;Quarmyne M;Tran E;Zhang Y;Fang T;Kan J;Chao NJ;Zhao L;Doan PL;Chute JP
通讯作者：
Chute JP