Hemoglobin synthesis in β-thalassemia: the properties of the free α-chains

Bank, Arthur

doi:10.1172/jci105779

Cited by 41 publications

(24 citation statements)

References 21 publications

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“…In patients with heterozygous P-thalassemia there is decreased P-globin production in the peripheral blood reticulocytes (4,(10)(11)(12). As expected, these patients have a pool of radioactive free a-chains in the peripheral blood larger than that found in control patients (6,7,9,13). We have previously described balanced globin chain synthesis in the bone marrow of patients with heterozygous P-thalassemia and related disorders (14)(15)(16).…”

Section: Introductionmentioning

confidence: 55%

“…The recovery of the total original radioactivity in the tetramer peak, without any residual radioactivity in the free a-chain pool, indicates clearly that the radioactive a-chains originally found in the pool were intact and able to combine with f-chains. Previous experiments have shown that the addition of free P-chains shifts radioactivity from the free a-chain pool in thalassemia major to the tetramer peak (6,7,9). In addition, the recovery of the total a-chain radioactivity in the tetramer peak after a storage period indicates that the free a-chain pool must be extremely small in comparison with the amount of globin in the tetramer peak.…”

Section: Resultsmentioning

confidence: 95%

“…peripheral blood and bone marrow from these patients (6,7,9). In patients with heterozygous P-thalassemia there is decreased P-globin production in the peripheral blood reticulocytes (4,(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

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Free α-Globin Pool in Human Bone Marrow

Gill¹,

Schwartz²

1973

J. Clin. Invest.

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Section: Introductionmentioning

confidence: 55%

Section: Resultsmentioning

confidence: 95%

See 1 more Smart Citation

Free α-Globin Pool in Human Bone Marrow

Gill¹,

Schwartz²

1973

J. Clin. Invest.

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“…[45][46][47][48] Additional early studies, interpreted in light of more recent work, indicate striking similarities between ␤-thalassemia and a class of diseases called "protein-aggregation disorders" (for review, see Khandros and Weiss 2 ). Common features include the accumulation of unstable, misfolded proteins that can be detoxified to some extent by cellular PQC systems, with disease ensuing when protective mechanisms are overwhelmed.…”

Section: Discussionmentioning

confidence: 99%

Integrated protein quality-control pathways regulate free α-globin in murine β-thalassemia

Khandros

Thom

D'Souza

et al. 2012

Blood

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Cells remove unstable polypeptides through protein quality-control (PQC) pathways such as ubiquitin-mediated proteolysis and autophagy. In the present study, we investigated how these pathways are used in ␤-thalassemia, a common hemoglobinopathy in which ␤-globin gene mutations cause the accumulation and precipitation of cytotoxic ␣-globin subunits. In ␤-thalassemic erythrocyte precursors, free ␣-globin was polyubiquitinated and degraded by the proteasome. These cells exhibited enhanced proteasome activity, and transcriptional profiling revealed coordinated induction of most proteasome subunits that was mediated by the stress-response transcription factor Nrf1. In isolated thalassemic cells, short-term proteasome inhibition blocked the degradation of free ␣-globin. In contrast, prolonged in vivo treatment of ␤-thalassemic mice with the proteasome inhibitor bortezomib did not enhance the accumulation of free ␣-globin. Rather, systemic proteasome inhibition activated compensatory proteotoxic stress-response mechanisms, including autophagy, which cooperated with ubiquitin-mediated proteolysis to degrade free ␣-globin in erythroid cells. Our findings show that multiple interregulated PQC responses degrade excess ␣-globin. Therefore, ␤-thalassemia fits into the broader framework of protein-aggregation disorders that use PQC pathways as cellprotective mechanisms. (Blood. 2012; 119(22):5265-5275) IntroductionThe production of functional hemoglobin A (HbA) tetramers (␣ 2 ␤ 2 ) requires the coordinated synthesis and assembly of ␣-and ␤-globin protein chains and iron-containing heme groups. Individually, all HbA components are toxic to RBCs and their precursors, as illustrated by ␤-thalassemias, a common hemoglobinopathy in which ␤-globin gene (HBB) mutations cause the buildup of free ␣-globin. 1 These unpaired ␣ chains initiate an oxidative damage cascade and form damaging precipitates that contribute largely to the clinical problems associated with ␤-thalassemia.The pathophysiology of ␤-thalassemia bears similarities to a diverse group of protein-aggregation diseases affecting multiple organs (for review, see Khandros and Weiss 2 ). These disorders, which include Parkinson disease, Alzheimer disease, Huntington disease, amyotrophic lateral sclerosis, and ␣ 1 -antitrypsin deficiency, are caused by the accumulation of unstable, relatively insoluble proteins. It is believed that the affected cells can detoxify and remove these damaging proteins via multiple interacting biochemical pathways called protein quality-control (PQC) pathways, but that disease ensues when such compensatory mechanisms are overwhelmed (for review, see Ciechanover and Brundin,3 Ding and Yin, 4 and Jaeger and Wyss-Coray 5 ). Cellular PQC systems include molecular chaperones, ubiquitin-mediated proteolysis, and autophagy. Several lines of evidence suggest that ␤-thalassemic erythroid cells use PQC pathways to detoxify free ␣-globin (for review, see Khandros and Weiss 2 ): (1) the clinical severity of ␤-thalassemia is proportional to the degree of ␣-glo...

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“…In β thalassemia, β-globin mutations cause αHb subunits to accumulate (5)(6)(7)(8). Free αHb (α-globin plus heme, or holo-α-globin) is a potent oxidant, catalyzing the production of ROSs, which damage erythroid precursors and mature erythrocytes (9).…”

Section: Introductionmentioning

confidence: 99%

An erythroid chaperone that facilitates folding of α-globin subunits for hemoglobin synthesis

Yu¹,

Kong²,

Doré³

et al. 2007

J. Clin. Invest.

103

104

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Erythrocyte precursors produce abundant α-and β-globin proteins, which assemble with each other to form hemoglobin A (HbA), the major blood oxygen carrier. αHb-stabilizing protein (AHSP) binds free α subunits reversibly to maintain their structure and limit their ability to generate reactive oxygen species. Accordingly, loss of AHSP aggravates the toxicity of excessive free α-globin caused by β-globin gene disruption in mice. Surprisingly, we found that AHSP also has important functions when free α-globin is limited. Thus, compound mutants lacking both Ahsp and 1 of 4 α-globin genes (genotype Ahsp -/-α-globin *α/αα ) exhibited more severe anemia and Hb instability than mice with either mutation alone. In vitro, recombinant AHSP promoted folding of newly translated α-globin, enhanced its refolding after denaturation, and facilitated its incorporation into HbA. Moreover, in erythroid precursors, newly formed free α-globin was destabilized by loss of AHSP. Therefore, in addition to its previously defined role in detoxification of excess α-globin, AHSP also acts as a molecular chaperone to stabilize nascent α-globin for HbA assembly. Our findings illustrate what we believe to be a novel adaptive mechanism by which a specialized cell coordinates high-level production of a multisubunit protein and protects against various synthetic imbalances.

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Hemoglobin synthesis in β-thalassemia: the properties of the free α-chains

Cited by 41 publications

References 21 publications

Free α-Globin Pool in Human Bone Marrow

Free α-Globin Pool in Human Bone Marrow

Integrated protein quality-control pathways regulate free α-globin in murine β-thalassemia

An erythroid chaperone that facilitates folding of α-globin subunits for hemoglobin synthesis

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