Integrated protein quality-control pathways regulate free (cid:1) -globin in murine (cid:2) -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 (cid:1) -thalassemia, a common hemoglobinopathy in which (cid:1) globin gene mutations cause the accumulation and precipitation of cytotoxic (cid:2) globin subunits. In (cid:1) -thalassemic erythrocyte precursors, free (cid:2) -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 transcriptionfactorNrf1.Inisolatedthalas-semiccells,short-termproteasomeinhibi- tion blocked the degradation of free (cid:2) -globin. In contrast, prolonged in vivo treatment of (cid:1) -thalassemic mice with the proteasome inhibitor bortezomib did not enhance the accumulation of free (cid:2) globin. Rather, systemic proteasome inhibition activated compensatory proteotoxic stress-response mechanisms, in-cludingautophagy,whichcooperatedwith ubiquitin-mediated proteolysis to degrade free (cid:2) -globin in erythroid cells. Our findings show that multiple interregulated PQC responses degrade excess (cid:2) -globin. Therefore, (cid:1) -thalassemia fits into the broader framework of protein-aggregation disorders that use PQC pathways as cell-protective mechanisms. ( Blood . 2012; 119(22):5265-5275)

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