PT  - JOURNAL ARTICLE
AU  - Lechauve, Christophe
AU  - Keith, Julia
AU  - Khandros, Eugene
AU  - Fowler, Stephanie
AU  - Mayberry, Kalin
AU  - Freiwan, Abdullah
AU  - Thom, Christopher S.
AU  - Delbini, Paola
AU  - Romero, Emilio Boada
AU  - Zhang, Jingjing
AU  - Motta, Irene
AU  - Tillman, Heather
AU  - Cappellini, M. Domenica
AU  - Kundu, Mondira
AU  - Weiss, Mitchell J.
TI  - The autophagy-activating kinase ULK1 mediates clearance of free α-globin in β-thalassemia
AID  - 10.1126/scitranslmed.aav4881
DP  - 2019 Aug 21
TA  - Science Translational Medicine
PG  - eaav4881
VI  - 11
IP  - 506
4099  - http://stm.sciencemag.org/content/11/506/eaav4881.short
4100  - http://stm.sciencemag.org/content/11/506/eaav4881.full
AB  - 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.