The autophagy-activating kinase ULK1 mediates clearance of free α-globin in β-thalassemia

Sci Transl Med. 2019 Aug 21;11(506):eaav4881. doi: 10.1126/scitranslmed.aav4881.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD34 / metabolism
  • Autophagy* / drug effects
  • Autophagy-Related Protein 5 / metabolism
  • Autophagy-Related Protein-1 Homolog / metabolism*
  • Disease Progression
  • Enzyme Activation / drug effects
  • Gene Deletion
  • Hematopoiesis / drug effects
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Mice
  • Phenotype
  • Reticulocytes / drug effects
  • Reticulocytes / metabolism
  • Reticulocytes / ultrastructure
  • Sirolimus / pharmacology
  • alpha-Globins / metabolism*
  • beta-Thalassemia / enzymology*
  • beta-Thalassemia / pathology*


  • Antigens, CD34
  • Autophagy-Related Protein 5
  • alpha-Globins
  • Autophagy-Related Protein-1 Homolog
  • Ulk1 protein, mouse
  • Sirolimus