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Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy.

Adenosine monophosphate-activated protein kinase (AMPK) is a conserved sensor of intracellular energy activated in response to low nutrient availability and environmental stress. In a screen for conserved substrates of AMPK, we identified ULK1 and ULK2, mammalian orthologs of the yeast protein kinase Atg1, which is required for autophagy. Genetic analysis of AMPK or ULK1 in mammalian liver and Caenorhabditis elegans revealed a requirement for these kinases in autophagy. In mammals, loss of AMPK or ULK1 resulted in aberrant accumulation of the autophagy adaptor p62 and defective mitophagy. Reconstitution of ULK1-deficient cells with a mutant ULK1 that cannot be phosphorylated by AMPK revealed that such phosphorylation is required for mitochondrial homeostasis and cell survival during starvation. These findings uncover a conserved biochemical mechanism coupling nutrient status with autophagy and cell survival.

Pubmed ID: 21205641

Authors

  • Egan DF
  • Shackelford DB
  • Mihaylova MM
  • Gelino S
  • Kohnz RA
  • Mair W
  • Vasquez DS
  • Joshi A
  • Gwinn DM
  • Taylor R
  • Asara JM
  • Fitzpatrick J
  • Dillin A
  • Viollet B
  • Kundu M
  • Hansen M
  • Shaw RJ

Journal

Science (New York, N.Y.)

Publication Data

January 28, 2011

Associated Grants

  • Agency: NCI NIH HHS, Id: 1P01CA120964
  • Agency: NCI NIH HHS, Id: 1P01CA120964-01A
  • Agency: NCI NIH HHS, Id: 5P30CA006516-43
  • Agency: NCI NIH HHS, Id: P01 CA120964
  • Agency: NCI NIH HHS, Id: P01 CA120964-05
  • Agency: NCI NIH HHS, Id: P30 CA006516
  • Agency: NCI NIH HHS, Id: P30 CA006516-43
  • Agency: NCI NIH HHS, Id: P30CA014195
  • Agency: NIDDK NIH HHS, Id: R01 DK080425
  • Agency: NIDDK NIH HHS, Id: R01 DK080425
  • Agency: NIDDK NIH HHS, Id: R01 DK080425-04
  • Agency: NIDDK NIH HHS, Id: R01 DK080425-05
  • Agency: NCI NIH HHS, Id: T32 CA009370
  • Agency: NCI NIH HHS, Id: T32 CA009370
  • Agency: NCI NIH HHS, Id: T32 CA009370-29
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • AMP-Activated Protein Kinases
  • Adaptor Proteins, Signal Transducing
  • Animals
  • Autophagy
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival
  • Energy Metabolism
  • Hepatocytes
  • Humans
  • Insulin
  • Intracellular Signaling Peptides and Proteins
  • Liver
  • Metformin
  • Mice
  • Mitochondria, Liver
  • Phenformin
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Signal Transduction
  • Transcription Factors