AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1

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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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Figure 1: Glucose starvation activates Ulk1 protein kinase through AMPK-dependent phosphorylation.
Figure 2: AMPK directly phosphorylates Ulk1 at Ser 317 and Ser 777.
Figure 3: AMPK-dependent Ulk1 Ser 317 and Ser 777 phosphorylation is required for Ulk1 activation in response to glucose starvation.
Figure 4: mTORC1 disrupts the Ulk1–AMPK interaction.
Figure 5: mTORC1 phosphorylates Ulk1 at Ser 757.
Figure 6: Phosphorylation of Ulk1 Ser 757 by mTORC1 inhibits the Ulk1–AMPK interaction.
Figure 7: AMPK phosphorylation is required for Ulk1 function in autophagy on glucose starvation.
Figure 8: Model of Ulk1 regulation by AMPK and mTORC1 in response to glucose signals.

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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

J.K. performed the experiments; M.K. and B.V. established the AMPK and Ulk1 knockout MEFs, respectively; J.K. and K.-L.G. designed the experiments, analysed data and wrote the paper. All authors discussed the results and commented on the manuscript.

Correspondence to Kun-Liang Guan.

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The authors declare no competing financial interests.

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Kim, J., Kundu, M., Viollet, B. et al. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13, 132–141 (2011) doi:10.1038/ncb2152

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