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 language | English |
|---|---|
| Pages (from-to) | 1457-1466 |
| Number of pages | 10 |
| Journal | Journal of Clinical Investigation |
| Volume | 114 |
| Issue number | 10 |
| Publication status | Published - Nov 2004 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Medicine(all)
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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 journal › Article
}
TY - JOUR
T1 - Loss of α-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates β-thalassemia
AU - Kong, Yi
AU - Zhou, Suiping
AU - Kihm, Anthony J.
AU - Katein, Anne M.
AU - Yu, Xiang
AU - Gell, David A.
AU - Mackay, Joel P.
AU - Adachi, Kazuhiko
AU - Foster-Brown, Linda
AU - Louden, Calvert S.
AU - Gow, Andrew J.
AU - Weiss, Mitchell J.
PY - 2004/11
Y1 - 2004/11
N2 - 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.
AB - 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.
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M3 - Article
C2 - 15545996
VL - 114
SP - 1457
EP - 1466
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 10
ER -