title: Loss of alpha-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates beta-thalassemia.
abstract: 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.
authors.affiliation: Cell and Molecular Biology Graduate Program, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Kong
authors.forename: Suiping
authors.initials: S
authors.lastname: Zhou
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Kihm
authors.forename: Anne M
authors.initials: AM
authors.lastname: Katein
authors.forename: Xiang
authors.initials: X
authors.lastname: Yu
authors.forename: David A
authors.initials: DA
authors.lastname: Gell
authors.forename: Joel P
authors.initials: JP
authors.lastname: Mackay
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Adachi
authors.forename: Linda
authors.initials: L
authors.lastname: Foster-Brown
authors.forename: Calvert S
authors.initials: CS
authors.lastname: Louden
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gow
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
mesh_terms: 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*
chemical_list: D006454:Hemoglobins; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins