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The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs

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 possib...

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Autores principales: Dite, Toby A., Ling, Naomi X. Y., Scott, John W., Hoque, Ashfaqul, Galic, Sandra, Parker, Benjamin L., Ngoei, Kevin R. W., Langendorf, Christopher G., O’Brien, Matthew T., Kundu, Mondira, Viollet, Benoit, Steinberg, Gregory R., Sakamoto, Kei, Kemp, Bruce E., Oakhill, Jonathan S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603566/
https://www.ncbi.nlm.nih.gov/pubmed/28924239
http://dx.doi.org/10.1038/s41467-017-00628-y
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author Dite, Toby A.
Ling, Naomi X. Y.
Scott, John W.
Hoque, Ashfaqul
Galic, Sandra
Parker, Benjamin L.
Ngoei, Kevin R. W.
Langendorf, Christopher G.
O’Brien, Matthew T.
Kundu, Mondira
Viollet, Benoit
Steinberg, Gregory R.
Sakamoto, Kei
Kemp, Bruce E.
Oakhill, Jonathan S.
author_facet Dite, Toby A.
Ling, Naomi X. Y.
Scott, John W.
Hoque, Ashfaqul
Galic, Sandra
Parker, Benjamin L.
Ngoei, Kevin R. W.
Langendorf, Christopher G.
O’Brien, Matthew T.
Kundu, Mondira
Viollet, Benoit
Steinberg, Gregory R.
Sakamoto, Kei
Kemp, Bruce E.
Oakhill, Jonathan S.
author_sort Dite, Toby A.
collection PubMed
description 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.
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spelling pubmed-56035662017-09-22 The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs Dite, Toby A. Ling, Naomi X. Y. Scott, John W. Hoque, Ashfaqul Galic, Sandra Parker, Benjamin L. Ngoei, Kevin R. W. Langendorf, Christopher G. O’Brien, Matthew T. Kundu, Mondira Viollet, Benoit Steinberg, Gregory R. Sakamoto, Kei Kemp, Bruce E. Oakhill, Jonathan S. Nat Commun Article 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. Nature Publishing Group UK 2017-09-18 /pmc/articles/PMC5603566/ /pubmed/28924239 http://dx.doi.org/10.1038/s41467-017-00628-y Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Dite, Toby A.
Ling, Naomi X. Y.
Scott, John W.
Hoque, Ashfaqul
Galic, Sandra
Parker, Benjamin L.
Ngoei, Kevin R. W.
Langendorf, Christopher G.
O’Brien, Matthew T.
Kundu, Mondira
Viollet, Benoit
Steinberg, Gregory R.
Sakamoto, Kei
Kemp, Bruce E.
Oakhill, Jonathan S.
The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs
title The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs
title_full The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs
title_fullStr The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs
title_full_unstemmed The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs
title_short The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs
title_sort autophagy initiator ulk1 sensitizes ampk to allosteric drugs
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603566/
https://www.ncbi.nlm.nih.gov/pubmed/28924239
http://dx.doi.org/10.1038/s41467-017-00628-y
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