| First Author | Khandros E | Year | 2012 |
| Journal | Blood | Volume | 119 |
| Issue | 22 | Pages | 5265-75 |
| PubMed ID | 22427201 | Mgi Jnum | J:185177 |
| Mgi Id | MGI:5427562 | Doi | 10.1182/blood-2011-12-397729 |
| Citation | Khandros E, et al. (2012) Integrated protein quality-control pathways regulate free alpha-globin in murine beta-thalassemia. Blood 119(22):5265-75 |
| abstractText | 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. |
