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

Yi Kong, Suiping Zhou, Anthony J. Kihm, Anne M. Katein, Xiang Yu, David A. Gell, Joel P. Mackay, Kazuhiko Adachi, Linda Foster-Brown, Calvert S. Louden, Andrew J. Gow, Mitchell J. Weiss

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Abstract

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.

Original languageEnglish
Pages (from-to)1457-1466
Number of pages10
JournalJournal of Clinical Investigation
Volume114
Issue number10
Publication statusPublished - Nov 2004
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kong, Y., Zhou, S., Kihm, A. J., Katein, A. M., Yu, X., Gell, D. A., Mackay, J. P., Adachi, K., Foster-Brown, L., Louden, C. S., Gow, A. J., & Weiss, M. J. (2004). Loss of α-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates β-thalassemia. Journal of Clinical Investigation, 114(10), 1457-1466.