The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs
Journal article
Dite, Toby A., Ling, Naomi, Scott, John W., Hoque, Ashfaqul, Galic, Sandra, Parker, Benjamin L., Ngoei, Kevin R.W., Langendorf, Christopher G., O'Brien, Matthew, Kundu, Mondira, Viollet, Benoit, Steinberg, Gregory R., Sakamoto, Kei, Kemp, Bruce and Oakhill, Jonathan S.. (2017). The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs. Nature Communications. 8(571), pp. 1 - 14. https://doi.org/10.1038/s41467-017-00628-y
Authors | Dite, Toby A., Ling, Naomi, Scott, John W., Hoque, Ashfaqul, Galic, Sandra, Parker, Benjamin L., Ngoei, Kevin R.W., Langendorf, Christopher G., O'Brien, Matthew, Kundu, Mondira, Viollet, Benoit, Steinberg, Gregory R., Sakamoto, Kei, Kemp, Bruce and Oakhill, Jonathan S. |
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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. |
Year | 2017 |
Journal | Nature Communications |
Journal citation | 8 (571), pp. 1 - 14 |
Publisher | Nature Publishing Group |
ISSN | 2041-1723 |
Digital Object Identifier (DOI) | https://doi.org/10.1038/s41467-017-00628-y |
Scopus EID | 2-s2.0-85029584631 |
Open access | Open access |
Page range | 1 - 14 |
Research Group | Mary MacKillop Institute for Health Research |
Publisher's version | License |
Place of publication | United Kingdom |
Editors | D. Gevaux and N. Scaplehorn |
https://acuresearchbank.acu.edu.au/item/8831v/the-autophagy-initiator-ulk1-sensitizes-ampk-to-allosteric-drugs
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OA_Dite_2017_The_autophagy_initiator_ULK1_sensitizes_AMPK.pdf | |
License: CC BY-NC 4.0 |
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