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.
Publication types
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
MeSH terms
- AMP-Activated Protein Kinases / metabolism*
- Adaptor Proteins, Signal Transducing / metabolism
- Animals
- Autophagy*
- Autophagy-Related Protein-1 Homolog
- Caenorhabditis elegans / metabolism
- Caenorhabditis elegans Proteins / genetics
- Caenorhabditis elegans Proteins / metabolism
- Cell Line
- Cell Line, Tumor
- Cell Survival
- Energy Metabolism
- Hepatocytes / metabolism
- Humans
- Insulin / metabolism
- Intracellular Signaling Peptides and Proteins / chemistry
- Intracellular Signaling Peptides and Proteins / genetics
- Intracellular Signaling Peptides and Proteins / metabolism*
- Liver / metabolism
- Metformin / pharmacology
- Mice
- Mitochondria, Liver / metabolism
- Mitochondria, Liver / ultrastructure
- Phenformin / pharmacology
- Phosphorylation
- Protein Serine-Threonine Kinases / chemistry
- Protein Serine-Threonine Kinases / genetics
- Protein Serine-Threonine Kinases / metabolism*
- Sequestosome-1 Protein
- Signal Transduction
- Transcription Factor TFIIH
- Transcription Factors / metabolism
Substances
- Adaptor Proteins, Signal Transducing
- Caenorhabditis elegans Proteins
- Gtf2h1 protein, mouse
- Insulin
- Intracellular Signaling Peptides and Proteins
- SQSTM1 protein, human
- Sequestosome-1 Protein
- Transcription Factors
- Transcription Factor TFIIH
- Metformin
- Phenformin
- Autophagy-Related Protein-1 Homolog
- Protein Serine-Threonine Kinases
- ULK1 protein, human
- Ulk1 protein, mouse
- AMP-Activated Protein Kinases