The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs

Toby A. Dite, Naomi X. Y. Ling, John W. Scott, Ashfaqul Hoque, Sandra Galic, Benjamin L. Parker, Kevin R. W. Ngoei, Christopher G. Langendorf, Matthew T. O’Brien, Mondira Kundu, Benoit Viollet, Gregory R. Steinberg, Kei Sakamoto, Bruce E. Kemp and Jonathan S. Oakhill ()
Additional contact information
Toby A. Dite: University of Melbourne
Naomi X. Y. Ling: University of Melbourne
John W. Scott: University of Melbourne
Ashfaqul Hoque: University of Melbourne
Sandra Galic: University of Melbourne
Benjamin L. Parker: The University of Sydney
Kevin R. W. Ngoei: University of Melbourne
Christopher G. Langendorf: University of Melbourne
Matthew T. O’Brien: University of Melbourne
Mondira Kundu: St Jude Children’s Research Hospital
Benoit Viollet: INSERM, U1016, Institut Cochin
Gregory R. Steinberg: McMaster University
Kei Sakamoto: University of Dundee
Bruce E. Kemp: University of Melbourne
Jonathan S. Oakhill: University of Melbourne

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract AMP-activated protein kinase (AMPK) is a metabolic stress-sensing enzyme responsible for maintaining cellular energy homeostasis. Activation of AMPK by salicylate and the thienopyridone A-769662 is critically dependent on phosphorylation of Ser108 in the β1 regulatory subunit. Here, we show a possible role for Ser108 phosphorylation in cell cycle regulation and promotion of pro-survival pathways in response to energy stress. We identify the autophagy initiator Unc-51-like kinase 1 (ULK1) as a β1-Ser108 kinase in cells. Cellular β1-Ser108 phosphorylation by ULK1 was dependent on AMPK β-subunit myristoylation, metabolic stress associated with elevated AMP/ATP ratio, and the intrinsic energy sensing capacity of AMPK; features consistent with an AMP-induced myristoyl switch mechanism. We further demonstrate cellular AMPK signaling independent of activation loop Thr172 phosphorylation, providing potential insight into physiological roles for Ser108 phosphorylation. These findings uncover new mechanisms by which AMPK could potentially maintain cellular energy homeostasis independently of Thr172 phosphorylation.

Date: 2017
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DOI: 10.1038/s41467-017-00628-y

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