title: Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy.
abstract: 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.
authors.affiliation: Molecular and Cell Biology Laboratory, Dulbecco Center for Cancer Research, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Egan
authors.forename: David B
authors.initials: DB
authors.lastname: Shackelford
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mihaylova
authors.forename: Sara
authors.initials: S
authors.lastname: Gelino
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Kohnz
authors.forename: William
authors.initials: W
authors.lastname: Mair
authors.forename: Debbie S
authors.initials: DS
authors.lastname: Vasquez
authors.forename: Aashish
authors.initials: A
authors.lastname: Joshi
authors.forename: Dana M
authors.initials: DM
authors.lastname: Gwinn
authors.forename: Rebecca
authors.initials: R
authors.lastname: Taylor
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.forename: James
authors.initials: J
authors.lastname: Fitzpatrick
authors.forename: Andrew
authors.initials: A
authors.lastname: Dillin
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Mondira
authors.initials: M
authors.lastname: Kundu
authors.forename: Malene
authors.initials: M
authors.lastname: Hansen
authors.forename: Reuben J
authors.initials: RJ
authors.lastname: Shaw
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D017173:Caenorhabditis elegans / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D004734:Energy Metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008930:Mitochondria, Liver / Q000378:metabolism / Q000648:ultrastructure; D010629:Phenformin / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D029742:Caenorhabditis elegans Proteins; C490981:Gtf2h1 protein, mouse; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D014157:Transcription Factors; D051758:Transcription Factor TFIIH; D008687:Metformin; D010629:Phenformin; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human; C112444:Ulk1 protein, mouse; D055372:AMP-Activated Protein Kinases