期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 11, 期 506, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aav4881
关键词
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资金
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01 DK61692]
- National Heart, Lung, and Blood Institute (NHLBI) [R01 HL114697]
- EMBO Long-Term Fellowship [ALTF 1526-2016]
- American Lebanese Syrian Associated Charities (ALSAC)
In beta-thalassemia, accumulated free alpha-globin forms intracellular precipitates that impair erythroid cell maturation and viability. Protein quality control systems mitigate beta-thalassemia pathophysiology by degrading toxic free alpha-globin, although the associated mechanisms are poorly understood. We show that loss of the autophagy-activating Unc-51-like kinase 1 (UlK1) gene in beta-thalassemic mice reduces autophagic clearance of alpha-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 alpha-globin precipitates and lessens pathologies in beta-thalassemic mice via an ULK1-dependent pathway. Similarly, rapamycin reduces free alpha-globin accumulation in erythroblasts derived from CD34(+) cells of beta-thalassemic individuals. Our findings define a drug-regulatable pathway for ameliorating beta-thalassemia.
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