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.
The autophagy-activating kinase ULK1 mediates clearance of free α-globin in β-thalassemia / C. Lechauve, J. Keith, E. Khandros, S. Fowler, K. Mayberry, A. Freiwan, C.S. Thom, P. Delbini, E.B. Romero, J. Zhang, I. Motta, H. Tillman, M.D. Cappellini, M. Kundu, M.J. Weiss. - In: SCIENCE TRANSLATIONAL MEDICINE. - ISSN 1946-6234. - 11:506(2019 Aug 21).
Titolo: | The autophagy-activating kinase ULK1 mediates clearance of free α-globin in β-thalassemia |
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Settore Scientifico Disciplinare: | Settore MED/09 - Medicina Interna |
Data di pubblicazione: | 21-ago-2019 |
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Tipologia: | Article (author) |
Digital Object Identifier (DOI): | http://dx.doi.org/10.1126/scitranslmed.aav4881 |
Appare nelle tipologie: | 01 - Articolo su periodico |
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