Erythroid maturation is coordinated to maximize the production of hemoglobin A heterotetramers (a2b2) and minimize the accumulation of potentially toxic free alpha or beta globin subunits. In beta thalassemia, mutations in the B globin gene cause a buildup of free alpha globin, which forms intracellular precipitates that impair erythroid cell maturation and viability. Protein quality-control systems mitigate beta thalassemia pathophysiology by degrading toxic free alpha globin. We show that loss of the Unc 51 like autophagy activating kinase gene Ulk1 in beta thalassemic mice reduces autophagic clearance of a 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 alpha globin precipitates and lessens pathologies in beta thalassemic mice, but not in those lacking Ulk1. Similarly, rapamycin reduces free α-globin accumulation in erythroblasts derived from B thalassemic patient CD34+ hematopoietic progenitors. Our findings identify a new, drug regulatable pathway for ameliorating beta thalassemia.

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