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

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 beta-thalassemia, a common hemoglobinopathy in which beta-globin gene mutations cause the accumulation and precipitation of cytotoxic alpha-globin subunits. In beta-thalassemic erythrocyte precursors, free alpha-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 alpha-globin. In contrast, prolonged in vivo treatment of beta-thalassemic mice with the proteasome inhibitor bortezomib did not enhance the accumulation of free alpha-globin. Rather, systemic proteasome inhibition activated compensatory proteotoxic stress-response mechanisms, including autophagy, which cooperated with ubiquitin-mediated proteolysis to degrade free alpha-globin in erythroid cells. Our findings show that multiple interregulated PQC responses degrade excess alpha-globin. Therefore, beta-thalassemia fits into the broader framework of protein-aggregation disorders that use PQC pathways as cell-protective mechanisms. (Blood. 2012; 119(22): 5265-5275)