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Science 331 (6016): 456-461

Copyright © 2011 by the American Association for the Advancement of Science

Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy

Daniel F. Egan,1 David B. Shackelford,1 Maria M. Mihaylova,1,2 Sara Gelino,4 Rebecca A. Kohnz,1 William Mair,1 Debbie S. Vasquez,1 Aashish Joshi,5 Dana M. Gwinn,1 Rebecca Taylor,1 John M. Asara,6 James Fitzpatrick,3 Andrew Dillin,1,2 Benoit Viollet,7 Mondira Kundu,5 Malene Hansen,4 Reuben J. Shaw1,2,*

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.

1 Molecular and Cell Biology Laboratory, Dulbecco Center for Cancer Research, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
2 Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
3 Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
4 Graduate School of Biomedical Sciences, Del E. Webb Neuroscience, Aging and Stem Cell Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
5 Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
6 Division of Signal Transduction, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
7 Inserm, U1016, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.

* To whom correspondence should be addressed. E-mail: shaw{at}salk.edu

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