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The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs

Author

Listed:
  • Toby A. Dite

    (University of Melbourne)

  • Naomi X. Y. Ling

    (University of Melbourne)

  • John W. Scott

    (University of Melbourne
    Australian Catholic University)

  • 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
    CNRS, UMR8104
    Université Paris Descartes, Sorbonne Paris Cité)

  • Gregory R. Steinberg

    (McMaster University)

  • Kei Sakamoto

    (University of Dundee
    Nestlé Institute of Health Sciences SA)

  • Bruce E. Kemp

    (University of Melbourne
    Australian Catholic University)

  • Jonathan S. Oakhill

    (University of Melbourne
    Australian Catholic University)

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.

Suggested Citation

  • 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 Violl, 2017. "The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00628-y
    DOI: 10.1038/s41467-017-00628-y
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