Article

AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1

  • Nature Cell Biology volume 13, pages 132141 (2011)
  • doi:10.1038/ncb2152
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Abstract

Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling.

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Acknowledgements

We thank members of the Guan lab for discussions and reagents. We would especially like to thank I. Lian and C. Fang for technical assistance, and M. Farquhar, K. Kudicka and T. Meerloo for help with the electron microscopy. This work was supported by NIH grants GM51586 and GM62694 (to K.-L.G.).

Author information

Affiliations

  1. Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92130, USA.

    • Joungmok Kim
    •  & Kun-Liang Guan
  2. Department of Pathology, St. Jude Children's Hospital, Memphis, TN 38105, USA.

    • Mondira Kundu
  3. INSERM U1016, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.

    • Benoit Viollet

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Kun-Liang Guan.

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