Loss of α-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates β-thalassemia

被引:133
作者
Kong, Y
Zhou, SP
Kihm, AJ
Katein, AM
Yu, X
Gell, DA
Mackay, JP
Adachi, K
Foster-Brown, L
Louden, CS
Gow, AJ
Weiss, MJ [1 ]
机构
[1] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Cell & Mol Biol Grad Program, Philadelphia, PA 19104 USA
[3] Astra Zeneca Pharmaceut LP, Safety Assessment, Wilmington, DE USA
[4] Univ Sydney, Sch Mol & Microbial Biosci, Sydney, NSW, Australia
关键词
D O I
10.1172/JCI200421982
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:1457 / 1466
页数:10
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