Loss of α-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates β-thalassemia
Loss of α-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates β-thalassemia
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DOI：
10.1172/jci200421982
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发表时间：
2004-11-01
影响因子：
15.9
通讯作者：
Weiss, MJ
中科院分区：
文献类型：
--
作者：
Kong, Y;Zhou, SP;Weiss, MJ
血红蛋白(Hb)A在红细胞发育过程中的产生是协调的，以最大限度地减少游离的α-和β-Hb亚基的有害影响，这两个亚基是不稳定的和具有细胞毒性的。α-Hb稳定蛋白(AHSP)是一种红系蛋白，能与α-Hb特异性结合并在体外阻止其沉淀，提示其在体内可能具有限制游离α-Hb毒性的功能。我们通过基因消融和生化研究来研究这种可能性。AHSP(-/-)红细胞含有血红蛋白沉淀物，寿命较短。在造血组织中，红系前体细胞数量增加，但细胞凋亡率增加。与不稳定的α-Hb一致，AHSI(-/-)红细胞含有增加的ROS和氧化损伤的证据。此外，纯化的重组AHSP还能抑制α-Hb在溶液中产生ROS。最后，AHSP的缺失加重了β-地中海贫血的表型，这是一种常见的遗传性贫血，以过量的游离α-Hb为特征。总之，这些数据支持一个模型，在该模型中，AHSP瞬时结合α-Hb，以稳定其构象，并在Hb A组装之前使其具有生化惰性。这一功能对于正常的红细胞生成是必不可少的，在更大程度上，对β-地中海贫血也是如此。我们的发现增加了改变AHSP表达水平可能调节人类β-地中海贫血严重程度的可能性。
Hemoglobin (Hb) A production during red blood cell development is coordinated to minimize the deleterious effects of free alpha- and beta-Hb subunits, which are unstable and cytotoxic. The alpha-Hb-stabilizing protein (AHSP) is an erythroid protein that specifically binds alpha-Hb and prevents its precipitation in vitro, which suggests that it may function to limit free alpha-Hb toxicities in vivo. We investigated this possibility through gene ablation and biochemical studies. AHSP(-/-) erythrocytes contained hemoglobin precipitates and were short-lived. In hematopoietic tissues, erythroid precursors were elevated in number but exhibited increased apoptosis. Consistent with unstable alpha-Hb, AHSI(-/-) erythrocytes contained increased ROS and evidence of oxidative damage. Moreover, purified recombinant AHSP inhibited ROS production by alpha-Hb in solution. Finally, loss of AHSP worsened the phenotype of beta-thalassemia, a common inherited anemia characterized by excess free alpha-Hb. Together, the data support a model in which AHSP binds alpha-Hb transiently to stabilize its conformation and render it biochemically inert prior to Hb A assembly. This function is essential for normal erythropoiesis and, to a greater extent, in beta-thalassemia. Our findings raise the possibility that altered AHSP expression levels could modulate the severity of beta-thalassemia in humans.