title: Integrated protein quality-control pathways regulate free α-globin in murine β-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 β-thalassemia, a common hemoglobinopathy in which β-globin gene mutations cause the accumulation and precipitation of cytotoxic α-globin subunits. In β-thalassemic erythrocyte precursors, free α-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 α-globin. In contrast, prolonged in vivo treatment of β-thalassemic mice with the proteasome inhibitor bortezomib did not enhance the accumulation of free α-globin. Rather, systemic proteasome inhibition activated compensatory proteotoxic stress-response mechanisms, including autophagy, which cooperated with ubiquitin-mediated proteolysis to degrade free α-globin in erythroid cells. Our findings show that multiple interregulated PQC responses degrade excess α-globin. Therefore, β-thalassemia fits into the broader framework of protein-aggregation disorders that use PQC pathways as cell-protective mechanisms.
authors.affiliation: Cell and Molecular Biology Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Khandros
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Thom
authors.forename: Janine
authors.initials: J
authors.lastname: D'Souza
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
mesh_terms: D000510:Alpha-Globulins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D015672:Erythroid Precursor Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D061988:Proteasome Inhibitors; D059748:Proteolysis / Q000187:drug effects*; D011719:Pyrazines / Q000494:pharmacology*; D054875:Ubiquitination / Q000187:drug effects* / Q000235:genetics; D017086:beta-Thalassemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
chemical_list: D000510:Alpha-Globulins; D000970:Antineoplastic Agents; D001897:Boronic Acids; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex