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The autophagy-activating kinase ULK1 mediates clearance of free ?-globin in ?-thalassemia.

ABSTRACT: In ?-thalassemia, accumulated free ?-globin forms intracellular precipitates that impair erythroid cell maturation and viability. Protein quality control systems mitigate ?-thalassemia pathophysiology by degrading toxic free ?-globin, although the associated mechanisms are poorly understood. We show that loss of the autophagy-activating Unc-51-like kinase 1 (Ulk1) gene in ?-thalassemic mice reduces autophagic clearance of ?-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 ?-globin precipitates and lessens pathologies in ?-thalassemic mice via an ULK1-dependent pathway. Similarly, rapamycin reduces free ?-globin accumulation in erythroblasts derived from CD34+ cells of ?-thalassemic individuals. Our findings define a drug-regulatable pathway for ameliorating ?-thalassemia.

SUBMITTER: Lechauve C

PROVIDER: S-EPMC7441525 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Lechauve Christophe C Keith Julia J Khandros Eugene E Fowler Stephanie S Mayberry Kalin K Freiwan Abdullah A Thom Christopher S CS Delbini Paola P Romero Emilio Boada EB Zhang Jingjing J Motta Irene I Tillman Heather H Cappellini M Domenica MD Kundu Mondira M Weiss Mitchell J MJ

Science translational medicine 20190801 506

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 (<i>Ulk1</i>) gene in β-thalassemic mice reduces autophagic clearance of α-globin in red blood cell precursors and exacerbates disease pheno ...[more]

PMID: 31434755

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Project description:Saturated fatty acid (SFA)-induced lipotoxicity is caused by the accumulation of reactive oxygen species (ROS), which is associated with damaged mitochondria. Moreover, lipotoxicity is crucial for the progression of nonalcoholic steatohepatitis (NASH). Autophagy is required for the clearance of protein aggregates or damaged mitochondria to maintain cellular metabolic homeostasis. The NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2)-KEAP1 (kelch like ECH associated protein 1) pathway is essential for the elimination of ROS. ULK1 (unc-51 like autophagy activating kinase 1; yeast Atg1) is involved in the initiation of autophagy; however, its role in lipotoxicity-induced cell death in hepatocytes and mouse liver has not been elucidated. We now show that ULK1 potentiates the interaction between KEAP1 and the autophagy adaptor protein SQSTM1/p62, thereby mediating NFE2L2 activation in a manner requiring SQSTM1-dependent autophagic KEAP1 degradation. Furthermore, ULK1 is required for the autophagic removal of damaged mitochondria and to enhance binding between SQSTM1 and PINK1 (PTEN induced kinase 1). This study demonstrates the molecular mechanisms underlying the cytoprotective role of ULK1 against lipotoxicity. Thus, ULK1 could represent a potential therapeutic target for the treatment of NASH.Abbreviations: ACTB: actin beta; CM-H2DCFDA:5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; CQ: chloroquine; CUL3: cullin 3; DMSO: dimethyl sulfoxide; GSTA1: glutathione S-transferase A1; HA: hemagglutinin; Hepa1c1c7: mouse hepatoma cells; HMOX1/HO-1: heme oxygenase 1; KEAP1: kelch like ECH associated protein 1; LPS: lipopolysaccharides; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK8/JNK: mitogen-activated protein kinase 8; MEF: mouse embryonic fibroblast; MFN1: mitofusin 1; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NASH: nonalcoholic steatohepatitis; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; NQO1: NAD(P)H quinone dehydrogenase 1; PA: palmitic acid; PARP: poly (ADP-ribose) polymerase 1; PINK1: PTEN induced kinase 1; PRKAA1/2: protein kinase AMP-activated catalytic subunits alpha1/2; PRKN/PARK2: parkin RBR E3 ubiquitin protein ligase; PRKC/PKC: protein kinase C; RBX1: ring-box 1; ROS: reactive oxygen species; SFA: saturated fatty acid; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUBA: tubulin alpha; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; ULK1: unc-51 like autophagy activating kinase 1.

Dataset Information

The autophagy-activating kinase ULK1 mediates clearance of free ?-globin in ?-thalassemia.

Publications

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

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