Integrated protein quality-control pathways regulate free ?-globin in murine ?-thalassemia.

ABSTRACT: 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 cell-protective mechanisms.

SUBMITTER: Khandros E 

PROVIDER: S-EPMC3369615 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature