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

Christophe Lechauve, Julia Keith, Eugene Khandros, Stephanie Fowler, Kalin Mayberry, Abdullah Freiwan, Christopher S. Thom, Paola Delbini, Emilio Boada Romero, Jingjing Zhang, Irene Motta, Heather Tillman, M. Domenica Cappellini, Mondira Kundu, Mitchell J. Weiss

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article numbereaav4881
JournalScience Translational Medicine
Volume11
Issue number506
DOIs
Publication statusPublished - Aug 21 2019

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Thalassemia
Globins
Autophagy
Phosphotransferases
Sirolimus
Erythroblasts
Erythroid Cells
Poisons
Quality Control
Genes
Cell Survival
Erythrocytes
Pathology
Phenotype
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Lechauve, C., Keith, J., Khandros, E., Fowler, S., Mayberry, K., Freiwan, A., ... Weiss, M. J. (2019). The autophagy-activating kinase ULK1 mediates clearance of free α-globin in β-thalassemia. Science Translational Medicine, 11(506), [eaav4881]. https://doi.org/10.1126/scitranslmed.aav4881

The autophagy-activating kinase ULK1 mediates clearance of free α-globin in β-thalassemia. / Lechauve, Christophe; Keith, Julia; Khandros, Eugene; Fowler, Stephanie; Mayberry, Kalin; Freiwan, Abdullah; Thom, Christopher S.; Delbini, Paola; Romero, Emilio Boada; Zhang, Jingjing; Motta, Irene; Tillman, Heather; Cappellini, M. Domenica; Kundu, Mondira; Weiss, Mitchell J.

In: Science Translational Medicine, Vol. 11, No. 506, eaav4881, 21.08.2019.

Research output: Contribution to journalArticle

Lechauve, C, Keith, J, Khandros, E, Fowler, S, Mayberry, K, Freiwan, A, Thom, CS, Delbini, P, Romero, EB, Zhang, J, Motta, I, Tillman, H, Cappellini, MD, Kundu, M & Weiss, MJ 2019, 'The autophagy-activating kinase ULK1 mediates clearance of free α-globin in β-thalassemia', Science Translational Medicine, vol. 11, no. 506, eaav4881. https://doi.org/10.1126/scitranslmed.aav4881
Lechauve, Christophe ; Keith, Julia ; Khandros, Eugene ; Fowler, Stephanie ; Mayberry, Kalin ; Freiwan, Abdullah ; Thom, Christopher S. ; Delbini, Paola ; Romero, Emilio Boada ; Zhang, Jingjing ; Motta, Irene ; Tillman, Heather ; Cappellini, M. Domenica ; Kundu, Mondira ; Weiss, Mitchell J. / The autophagy-activating kinase ULK1 mediates clearance of free α-globin in β-thalassemia. In: Science Translational Medicine. 2019 ; Vol. 11, No. 506.
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