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Loss of alpha-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates beta-thalassemia
journal contributionposted 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 Î±- and Î²-Hb subunits, which are unstable and cytotoxic. The Î±-Hb-stabilizing protein (AHSP) is an erythroid protein that specifically binds Î±-Hb and prevents its precipitation in vitro, which suggests that it may function to limit free Î±-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 Î±-Hb, AHSP-/- erythrocytes contained increased ROS and evidence of oxidative damage. Moreover, purified recombinant AHSP inhibited ROS production by Î±-Hb in solution. Finally, loss of AHSP worsened the phenotype of Î²-thalassemia, a common inherited anemia characterized by excess free Î±-Hb. Together, the data support a model in which AHSP binds Î±-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 Î²-thalassemia. Our findings raise the possibility that altered AHSP expression levels could modulate the severity of Î²-thalassemia in humans.
Publication titleJournal of Clinical Investigation
Department/SchoolMenzies Institute for Medical Research
PublisherAmer Soc Clinical Investigation Inc
Place of publication35 Research Dr, Ste 300, Ann Arbor, USA, Mi, 48103