J Clin Invest. 2007 July 2; 117(7): 1746–1749.
Published online 2007 July 2. doi: 10.1172/JCI32362.
Published online 2007 July 2. doi: 10.1172/JCI32362.
Arthur Bank
Department of Medicine and Department of Genetics and Development, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Department of Medicine and Department of Genetics and Development, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Recently, the small protein α hemoglobin–stabilizing protein (AHSP) was identified and found to specifically bind α-globin, stabilize its structure, and limit the toxic effects of excess α-globin, which are manifest in the inherited blood disorder β thalassemia. In this issue of the JCI, Yu, Weiss, and colleagues show that AHSP is also critical to the formation and stabilization of normal amounts of hemoglobin, even when α-globin is deficient, indicating unique and previously unidentified roles for this molecule
Now, in this issue of the JCI (11), Yu, Weiss, and colleagues show that AHSP is a much more adroit Hb helper, facilitating even more important new “twists” in Hb assembly. The authors show that AHSP is important not only for dealing with newly synthesized excess α-globin, but also in the assembly of normal Hb tetramers. In these new studies, Ahsp–/– mice with mild α thalassemia were examined. This condition is associated with a deficit of α-globin and an excess of β-globin, so no specific role for AHSP was expected to be required in these mice. However, Ahsp–/– mice with α thalassemia were found to be more anemic than either Ahsp–/– mice or α thalassemic mice. If the role of AHSP is only to stabilize apo-α-globin and αHb, why should its absence have any effect?
The authors provide some of the possible answers (11). They show that the anemia in the Ahsp–/– mice with α thalassemia is accompanied by an excess of precipitated β-globin chains in the membrane of erythroid cells (Figure 1C), which are present in much greater quantities than in either Ahsp–/– mice or α thalassemic mice. Thus, AHSP is required for the assembly of normally synthesized excess β chains into functional HbA in these mice. Even the presence of small amounts of newly synthesized apo-α-globin and αHb not stabilized by AHSP results in the inability of excess β-globin chains to be efficiently transferred into HbA in these α thalassemic mice. Thus, without AHSP, excess β-globin and βHb are also unstable and deposited in the red cell membrane, leading to increased oxidative damage and more severe anemia (Figure 1C). The authors show that levels of ROS are greatly increased in the double mutants as compared with single mutants, reflecting this pathology (11). They also demonstrate that the deleterious effects of AHSP deficiency increase in marrow nucleated erythroid cell populations as they accumulate more globin and Hb, confirming and extending previous results (12).
Potential roles for AHSP as an intermediate in the optimal formation of normal Hbαβ dimers and/or tetramers remain to be determined. It is clear from this study (11), however, that AHSP is necessary for more than just chaperoning α-globin around: it is also necessary for normal HbA assembly, especially when there is an imbalance in either α- or β-globin.
The results of several elegant in vitro experiments in this study (11) also provide new details regarding the way AHSP handles α-globin in cells. Newly synthesized α-globin chains, even nascent α-globin chains on ribosomes, are rapidly complexed to AHSP in cell-free systems. More HbA is formed in the presence of AHSP than without it. AHSP increases the resistance of apo-α-globin to proteolysis by trypsin by promoting the proper folding of α-globin in the αHb-AHSP complex. Even after denaturation of apo-α-globin chains, their renaturation is shown to be strongly promoted by the presence of AHSP (11).
The authors provide some of the possible answers (11). They show that the anemia in the Ahsp–/– mice with α thalassemia is accompanied by an excess of precipitated β-globin chains in the membrane of erythroid cells (Figure 1C), which are present in much greater quantities than in either Ahsp–/– mice or α thalassemic mice. Thus, AHSP is required for the assembly of normally synthesized excess β chains into functional HbA in these mice. Even the presence of small amounts of newly synthesized apo-α-globin and αHb not stabilized by AHSP results in the inability of excess β-globin chains to be efficiently transferred into HbA in these α thalassemic mice. Thus, without AHSP, excess β-globin and βHb are also unstable and deposited in the red cell membrane, leading to increased oxidative damage and more severe anemia (Figure 1C). The authors show that levels of ROS are greatly increased in the double mutants as compared with single mutants, reflecting this pathology (11). They also demonstrate that the deleterious effects of AHSP deficiency increase in marrow nucleated erythroid cell populations as they accumulate more globin and Hb, confirming and extending previous results (12).
Potential roles for AHSP as an intermediate in the optimal formation of normal Hbαβ dimers and/or tetramers remain to be determined. It is clear from this study (11), however, that AHSP is necessary for more than just chaperoning α-globin around: it is also necessary for normal HbA assembly, especially when there is an imbalance in either α- or β-globin.
The results of several elegant in vitro experiments in this study (11) also provide new details regarding the way AHSP handles α-globin in cells. Newly synthesized α-globin chains, even nascent α-globin chains on ribosomes, are rapidly complexed to AHSP in cell-free systems. More HbA is formed in the presence of AHSP than without it. AHSP increases the resistance of apo-α-globin to proteolysis by trypsin by promoting the proper folding of α-globin in the αHb-AHSP complex. Even after denaturation of apo-α-globin chains, their renaturation is shown to be strongly promoted by the presence of AHSP (11).
In summary, AHSP has been identified as a unique Hb helper, a molecular chaperone required for normal Hb assembly. Yu, Weiss, and colleagues make the interesting suggestion that AHSP provides a selective advantage for the survival of red cells, especially when there are significant amounts of either excess α- or β-globin present (11). Interestingly, the red cells of patients with α and β thalassemia are more resistant to the severe form of malaria than normal cells (13). The evolution of AHSP may have permitted the preferential survival of these cells. Without AHSP, the thalassemic red cells might not have survived, while with it, they are able to. Thus, AHSP may have evolved to give erythroid progenitors an “edge,” especially when mutations occur that lead to significantly unbalanced α- or β-globin levels. Then, throughout evolution, the AHSP-expressing cells with globin mutations may have been further selected to survive because these cells prevented fatal malarial infection.
Also, because of its effects on preventing α-globin denaturation and promoting renaturation, AHSP may provide an additional selective advantage to red cells under conditions of oxidative stress induced by drugs that cause a greater susceptibility to hemolysis. AHSP may also be useful to red cells in iron deficiency in which heme availability is limited and apo-α-globin levels are increased. These functions may represent additional evolution-based roles for AHSP in the stabilization of red cells in the presence of environmental factors that alter Hb’s critical equilibrium. No human disease resembling AHSP deficiency has yet been described, although associations between the severity of β thalassemia in patients with variations in AHSP are being explored (14, 15). In a case of a naturally occurring human α-globin chain mutation, in which the binding site for αHb-AHSP complex formation is altered, there is decreased stability of the resulting human Hb (16).
Are there other Hb helpers, be they specific α-globin chaperones or other erythroid-specific or ubiquitous molecules, with which AHSP interacts? It is known that the transcription factors GATA-1, OCT-1, and EKLF are required for AHSP expression (17, 18). How does AHSP interact with these and other transcription factors and intermediates affecting heme biosynthesis and posttranscriptional modifiers in red cells in the process of Hb synthesis and assembly? These and other questions regarding our understanding of Hb regulation remain. We are also still in the dark about what controls the differentiation of nucleated red cells and their enucleation, what regulates the filling of red cells with the desired amount of Hb, and how that amount is maintained until red cell death. Does AHSP function in these events? Weiss et al. (11) have given us a start by identifying an important Hb helper, but there is plenty of room for researchers to discover other Hb helpers and to shed more light on this subject.
Also, because of its effects on preventing α-globin denaturation and promoting renaturation, AHSP may provide an additional selective advantage to red cells under conditions of oxidative stress induced by drugs that cause a greater susceptibility to hemolysis. AHSP may also be useful to red cells in iron deficiency in which heme availability is limited and apo-α-globin levels are increased. These functions may represent additional evolution-based roles for AHSP in the stabilization of red cells in the presence of environmental factors that alter Hb’s critical equilibrium. No human disease resembling AHSP deficiency has yet been described, although associations between the severity of β thalassemia in patients with variations in AHSP are being explored (14, 15). In a case of a naturally occurring human α-globin chain mutation, in which the binding site for αHb-AHSP complex formation is altered, there is decreased stability of the resulting human Hb (16).
Are there other Hb helpers, be they specific α-globin chaperones or other erythroid-specific or ubiquitous molecules, with which AHSP interacts? It is known that the transcription factors GATA-1, OCT-1, and EKLF are required for AHSP expression (17, 18). How does AHSP interact with these and other transcription factors and intermediates affecting heme biosynthesis and posttranscriptional modifiers in red cells in the process of Hb synthesis and assembly? These and other questions regarding our understanding of Hb regulation remain. We are also still in the dark about what controls the differentiation of nucleated red cells and their enucleation, what regulates the filling of red cells with the desired amount of Hb, and how that amount is maintained until red cell death. Does AHSP function in these events? Weiss et al. (11) have given us a start by identifying an important Hb helper, but there is plenty of room for researchers to discover other Hb helpers and to shed more light on this subject.
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