Protein Quality Control During Erythropoiesis and Hemoglobin Synthesis

Abstract

Synopsis Erythrocytes must regulate hemoglobin synthesis to limit the toxicities of unstable free globin chain subunits. This is particularly relevant in β-thalassemia, where β globin deficiency causes accumulation of free α globin, which forms intracellular precipitates that destroy erythroid precursors. Experimental evidence accumulated over more than 40 years indicates that erythroid cells can neutralize moderate amounts of free α globin through generalized protein quality control mechanisms including molecular chaperones, the ubiquitin proteasome system and autophagy. In many ways, β-thalassemia resembles protein aggregation disorders of nervous system, liver and other tissues, which occur when levels of unstable proteins exceed cellular compensatory mechanisms. It is likely that information gained through studies of non-erythroid protein aggregation disorders can be exploited to further understand and perhaps treat β-thalassemia.

Insights into Hemoglobin Assembly through in Vivo Mutagenesis of α-Hemoglobin Stabilizing Protein

“…Prior studies indicate two potential functions for AHSP during normal and pathologic erythropoiesis (8,26,63). First, AHSP acts as a molecular chaperone to bind and stabilize nascent ␣-globin folding intermediates prior to reaction with ␤-globin and assembly into HbA (Fig.…”

“…Erythroid cells contain protective mechanisms to balance HbA synthesis and reduce the toxicity of free globin chains (8). For example, ␣-hemoglobin stabilizing protein (AHSP) binds ␣ but not ␤ chains or intact HbA (9,10) and inhibits denaturation of free ␣-globin in vitro (9,10).…”

Characterization of the TGF-β1 signaling abnormalities in the Gata1low mouse model of myelofibrosis

“…The biological consequences predicted by these abnormalities are consistent with the Gata1 low phenotype. Alterations of TGF-b signaling predict increased levels of osteoblast differentiation in BM but not in spleen from Gata1 low mice, increased apoptosis and G1 arrest both in BM and spleen but reduced ubiquitin-mediated proteolysis, a pathway indispensable for erythroid maturation, 36 in BM only and activation of mammalian target of rapamycin (mTOR), a positive regulator of translation which improves erythropoiesis, 37 in spleen (Table 5). …”

Pomalidomide reverses γ-globin silencing through the transcriptional reprogramming of adult hematopoietic progenitors

“…2 Therefore, b-hemoglobinopathies have been the focus of numerous studies aimed at elucidating the molecular pathophysiology of these diseases and developing new therapeutic strategies. 3 Although the pathophysiology of b-thalassemia and SCD differ, [4][5][6][7][8][9] clinical symptoms do not manifest before birth because b-globin chains are expressed postnatally. Because reactivation of fetal hemoglobin (HbF) ameliorates anemia and associated complications of SCD, 10 strategies for HbF induction have long been pursued as therapeutic options.…”