The autophagy-activating kinase ULK1 mediates clearance of free α-globin in ß-thalassemia.
Sci Transl Med
; 11(506)2019 08 21.
Article
em En
| MEDLINE
| ID: mdl-31434755
ABSTRACT
In ß-thalassemia, accumulated free α-globin forms intracellular precipitates that impair erythroid cell maturation and viability. Protein quality control systems mitigate ß-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 ß-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 ß-thalassemic mice via an ULK1-dependent pathway. Similarly, rapamycin reduces free α-globin accumulation in erythroblasts derived from CD34+ cells of ß-thalassemic individuals. Our findings define a drug-regulatable pathway for ameliorating ß-thalassemia.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Autofagia
/
Talassemia beta
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Alfa-Globinas
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Proteína Homóloga à Proteína-1 Relacionada à Autofagia
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article