Unc 51–like autophagy-activating kinase (ULK1) mediates clearance of free α-globin in β-thalassemia

Abstract

AbstractErythroid maturation is coordinated to maximize the production of hemoglobin A heterotetramers (α2β2) and minimize the accumulation of potentially toxic free α- or β-globin subunits. In β-thalassemia, mutations in the β-globin gene cause a build-up of free α-globin, which forms intracellular precipitates that impair erythroid cell maturation and viability. Protein quality-control systems mitigate β-thalassemia pathophysiology by degrading toxic free α-globin. We show that loss of the Unc 51–like autophagy-activating kinase geneUlk1in β-thalassemic mice reduces autophagic clearance of α-globin in red cell precursors and exacerbates disease phenotypes, whereas inactivation of the canonical autophagy geneAtg5has minimal effects. Systemic treatment with rapamycin to inhibit the ULK1 inhibitor mTORC1 reduces α-globin precipitates and lessens pathologies in β-thalassemic mice, but not in those lackingUlk1. Similarly, rapamycin reduces free α-globin accumulation in erythroblasts derived from β-thalassemic patient CD34+hematopoietic progenitors. Our findings identify a new, drug-regulatable pathway for ameliorating β-thalassemia.One Sentence SummaryRapamycin alleviates β-thalassemia by stimulating ULK1-dependent autophagy of toxic free α-globin.