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

Erythroid 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 gene Ulk1 in β-thalassemic mice reduces autophagic clearance of α-globin in red cell precursors and exacerbates disease phenotypes, whereas inactivation of the canonical autophagy gene Atg5 has 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 lacking Ulk1. 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 Summary Rapamycin alleviates β-thalassemia by stimulating ULK1-dependent autophagy of toxic free α-globin.