Loss of alpha-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates beta-thalassemia.
Hemoglobin (Hb) A production during red blood cell development is coordinated to minimize the deleterious effects of free alpha- and beta-Hb subunits, which are unstable and cytotoxic. The alpha-Hb-stabilizing protein (AHSP) is an erythroid protein that specifically binds alpha-Hb and prevents its precipitation in vitro, which suggests that it may function to limit free alpha-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 alpha-Hb, AHSP(-/-) erythrocytes contained increased ROS and evidence of oxidative damage. Moreover, purified recombinant AHSP inhibited ROS production by alpha-Hb in solution. Finally, loss of AHSP worsened the phenotype of beta-thalassemia, a common inherited anemia characterized by excess free alpha-Hb. Together, the data support a model in which AHSP binds alpha-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 beta-thalassemia. Our findings raise the possibility that altered AHSP expression levels could modulate the severity of beta-thalassemia in humans.
Kong
Yi
Y
Cell and Molecular Biology Graduate Program, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Zhou
Suiping
S
Kihm
Anthony J
AJ
Katein
Anne M
AM
Yu
Xiang
X
Gell
David A
DA
Mackay
Joel P
JP
Adachi
Kazuhiko
K
Foster-Brown
Linda
L
Louden
Calvert S
CS
Gow
Andrew J
AJ
Weiss
Mitchell J
MJ
D000818:Animals; D017209:Apoptosis; D004912:Erythrocytes / Q000378:metabolism* / Q000473:pathology; D004920:Erythropoiesis; D006366:Heinz Bodies / Q000737:chemistry / Q000378:metabolism; D006454:Hemoglobins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D006579:Heterozygote; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D011487:Protein Conformation; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D017086:beta-Thalassemia / Q000378:metabolism*
D006454:Hemoglobins; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins