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- Title
The autophagy-activating kinase ULK1 mediates clearance of free α-globin in β-thalassemia.
- Authors
Lechauve, Christophe; Keith, Julia; Khandros, Eugene; Fowler, Stephanie; Mayberry, Kalin; Freiwan, Abdullah; Thom, Christopher S.; Delbini, Paola; Romero, Emilio Boada; Zhang, Jingjing; Motta, Irene; Tillman, Heather; Cappellini, M. Domenica; Kundu, Mondira; Weiss, Mitchell J.
- Abstract
Unclogging red blood cells: In β-thalassemia, a genetic disorder caused by mutations in the β-globin subunit of adult hemoglobin, the pathological consequences are caused by two problems. One is a shortage of adult hemoglobin that can function to transport oxygen, while the other is a buildup of excess α-globin subunits, which damages the red blood cells and thus further impairs oxygen transport in the body. Using mouse models of β-thalassemia as well as patient-derived cells, Lechauve et al. determined that autophagy-activating kinase ULK1 plays a key role in the clearance of accumulated α-globin. The authors also showed that the drug rapamycin stimulates ULK1-dependent autophagy and thus facilitates α-globin clearance. In β-thalassemia, accumulated free α-globin forms intracellular precipitates that impair erythroid cell maturation and viability. Protein quality control systems mitigate β-thalassemia pathophysiology by degrading toxic free α-globin, although the associated mechanisms are poorly understood. We show that loss of the autophagy-activating Unc-51–like kinase 1 (Ulk1) gene in β-thalassemic mice reduces autophagic clearance of α-globin in red blood cell precursors and exacerbates disease phenotypes, whereas inactivation of the canonical autophagy-related 5 (Atg5) gene has relatively minor effects. Systemic treatment with the mTORC1 inhibitor rapamycin reduces α-globin precipitates and lessens pathologies in β-thalassemic mice via an ULK1-dependent pathway. Similarly, rapamycin reduces free α-globin accumulation in erythroblasts derived from CD34+ cells of β-thalassemic individuals. Our findings define a drug-regulatable pathway for ameliorating β-thalassemia.
- Publication
Science Translational Medicine, 2019, Vol 11, Issue 506, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aav4881