The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs.
Identifieur interne : 000584 ( PubMed/Curation ); précédent : 000583; suivant : 000585The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs.
Auteurs : Toby A. Dite [Australie] ; Naomi X Y. Ling [Australie] ; John W. Scott [Australie] ; Ashfaqul Hoque [Australie] ; Sandra Galic [Australie] ; Benjamin L. Parker [Australie] ; Kevin R W. Ngoei [Australie] ; Christopher G. Langendorf [Australie] ; Matthew T. O'Brien [Australie] ; Mondira Kundu [États-Unis] ; Benoit Viollet [France] ; Gregory R. Steinberg [Canada] ; Kei Sakamoto [Royaume-Uni] ; Bruce E. Kemp [Australie] ; Jonathan S. Oakhill [Australie]Source :
- Nature communications [ 2041-1723 ] ; 2017.
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.AMPK is involved in sensing of metabolic stress. The authors show that the autophagy initiator ULK1 phosphorylates β1-Ser108 on the regulatory β1-subunit, sensitizing AMPK to allosteric drugs, and activates signaling pathways that appear independent of Thr172 phosphorylation in the kinase activation loop.
DOI: 10.1038/s41467-017-00628-y
PubMed: 28924239
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<front><div type="abstract" xml:lang="en">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.AMPK is involved in sensing of metabolic stress. The authors show that the autophagy initiator ULK1 phosphorylates β1-Ser108 on the regulatory β1-subunit, sensitizing AMPK to allosteric drugs, and activates signaling pathways that appear independent of Thr172 phosphorylation in the kinase activation loop.</div>
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<Abstract><AbstractText>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.AMPK is involved in sensing of metabolic stress. The authors show that the autophagy initiator ULK1 phosphorylates β1-Ser108 on the regulatory β1-subunit, sensitizing AMPK to allosteric drugs, and activates signaling pathways that appear independent of Thr172 phosphorylation in the kinase activation loop.</AbstractText>
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<ForeName>Toby A</ForeName>
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<AffiliationInfo><Affiliation>Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, Australia.</Affiliation>
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<AffiliationInfo><Affiliation>Université Paris Descartes, Sorbonne Paris Cité, Paris, France.</Affiliation>
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<Author ValidYN="Y"><LastName>Sakamoto</LastName>
<ForeName>Kei</ForeName>
<Initials>K</Initials>
<AffiliationInfo><Affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Scotland, UK.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Nestlé Institute of Health Sciences SA, Lausanne, Switzerland.</Affiliation>
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<Author ValidYN="Y"><LastName>Kemp</LastName>
<ForeName>Bruce E</ForeName>
<Initials>BE</Initials>
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<AffiliationInfo><Affiliation>Protein Chemistry & Metabolism, St Vincent's Institute of Medical Research, University of Melbourne, Melbourne, VIC, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Oakhill</LastName>
<ForeName>Jonathan S</ForeName>
<Initials>JS</Initials>
<AffiliationInfo><Affiliation>Metabolic Signalling Laboratory, St Vincent's Institute of Medical Research, University of Melbourne, Melbourne, VIC, Australia. joakhill@svi.edu.au.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, Australia. joakhill@svi.edu.au.</Affiliation>
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<Language>eng</Language>
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<Month>09</Month>
<Day>18</Day>
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