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

Research output: Contribution to journalArticle

118 Citations (Scopus)

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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Thalassemia
Erythropoiesis
Hemoglobins
Proteins
Hemoglobin A
Erythrocytes
Hemoglobin Subunits
Anemia
Apoptosis
Phenotype

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kong, Y., Zhou, S., Kihm, A. J., Katein, A. M., Yu, X., Gell, D. A., ... Weiss, M. J. (2004). Loss of α-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates β-thalassemia. Journal of Clinical Investigation, 114(10), 1457-1466.

Loss of α-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates β-thalassemia. / Kong, Yi; Zhou, Suiping; Kihm, Anthony J.; Katein, Anne M.; Yu, Xiang; Gell, David A.; Mackay, Joel P.; Adachi, Kazuhiko; Foster-Brown, Linda; Louden, Calvert S.; Gow, Andrew J.; Weiss, Mitchell J.

In: Journal of Clinical Investigation, Vol. 114, No. 10, 11.2004, p. 1457-1466.

Research output: Contribution to journalArticle

Kong, Y, Zhou, S, Kihm, AJ, Katein, AM, Yu, X, Gell, DA, Mackay, JP, Adachi, K, Foster-Brown, L, Louden, CS, Gow, AJ & Weiss, MJ 2004, 'Loss of α-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates β-thalassemia', Journal of Clinical Investigation, vol. 114, no. 10, pp. 1457-1466.
Kong Y, Zhou S, Kihm AJ, Katein AM, Yu X, Gell DA et al. Loss of α-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates β-thalassemia. Journal of Clinical Investigation. 2004 Nov;114(10):1457-1466.
Kong, Yi ; Zhou, Suiping ; Kihm, Anthony J. ; Katein, Anne M. ; Yu, Xiang ; Gell, David A. ; Mackay, Joel P. ; Adachi, Kazuhiko ; Foster-Brown, Linda ; Louden, Calvert S. ; Gow, Andrew J. ; Weiss, Mitchell J. / Loss of α-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates β-thalassemia. In: Journal of Clinical Investigation. 2004 ; Vol. 114, No. 10. pp. 1457-1466.
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