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Loss of alpha-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates beta-thalassemia

journal contribution
posted on 2023-05-17, 02:58 authored by Kong, Y, Zhou, S, Kihm, AJ, Katein, AM, Yu, X, David GellDavid Gell, Mackay, JP, Adachi, K, Foster-Brown, L, Louden, CS, Gow, AJ, Weiss, MJ
Hemoglobin (Hb) A production during red blood cell development is coordinated to minimize the deleterious effects of free α- and β-Hb subunits, which are unstable and cytotoxic. The α-Hb-stabilizing protein (AHSP) is an erythroid protein that specifically binds α-Hb and prevents its precipitation in vitro, which suggests that it may function to limit free α-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 α-Hb, AHSP-/- erythrocytes contained increased ROS and evidence of oxidative damage. Moreover, purified recombinant AHSP inhibited ROS production by α-Hb in solution. Finally, loss of AHSP worsened the phenotype of β-thalassemia, a common inherited anemia characterized by excess free α-Hb. Together, the data support a model in which AHSP binds α-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 β-thalassemia. Our findings raise the possibility that altered AHSP expression levels could modulate the severity of β-thalassemia in humans.


Publication title

Journal of Clinical Investigation










Menzies Institute for Medical Research


Amer Soc Clinical Investigation Inc

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35 Research Dr, Ste 300, Ann Arbor, USA, Mi, 48103

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Expanding knowledge in the biological sciences

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