The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs
Identifieur interne : 000237 ( Main/Exploration ); précédent : 000236; suivant : 000238The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs
Auteurs : Toby A. Dite ; Naomi X. Y. Ling ; John W. Scott ; Ashfaqul Hoque ; Sandra Galic ; Benjamin L. Parker [Australie] ; Kevin R. W. Ngoei ; Christopher G. Langendorf ; Matthew T. O Rien ; Mondira Kundu [États-Unis] ; Benoit Viollet [France] ; Gregory R. Steinberg ; Kei Sakamoto [Royaume-Uni, Suisse] ; Bruce E. Kemp ; Jonathan S. OakhillSource :
- 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.
Url:
DOI: 10.1038/s41467-017-00628-y
PubMed: 28924239
PubMed Central: 5603566
Affiliations:
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O Rien</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2179 088X</institution-id><institution-id institution-id-type="GRID">grid.1008.9</institution-id><institution>Protein Chemistry & Metabolism, St Vincent’s Institute of Medical Research,</institution><institution>University of Melbourne,</institution></institution-wrap>Melbourne, VIC Australia</nlm:aff><wicri:noCountry code="subfield">VIC Australia</wicri:noCountry></affiliation></author><author><name sortKey="Kundu, Mondira" sort="Kundu, Mondira" uniqKey="Kundu M" first="Mondira" last="Kundu">Mondira Kundu</name><affiliation wicri:level="2"><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0224 711X</institution-id><institution-id institution-id-type="GRID">grid.240871.8</institution-id><institution>Department of Pathology,</institution><institution>St Jude Children’s Research Hospital,</institution></institution-wrap>Memphis, TN USA</nlm:aff><country>États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Memphis</wicri:cityArea></affiliation></author><author><name sortKey="Viollet, Benoit" sort="Viollet, Benoit" uniqKey="Viollet B" first="Benoit" last="Viollet">Benoit Viollet</name><affiliation wicri:level="1"><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0643 431X</institution-id><institution-id institution-id-type="GRID">grid.462098.1</institution-id><institution>INSERM, U1016, Institut Cochin,</institution></institution-wrap>Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Paris</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2112 9282</institution-id><institution-id institution-id-type="GRID">grid.4444.0</institution-id><institution>CNRS, UMR8104,</institution></institution-wrap>Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Paris</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="Aff8"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2188 0914</institution-id><institution-id institution-id-type="GRID">grid.10992.33</institution-id><institution>Université Paris Descartes, Sorbonne Paris Cité,</institution></institution-wrap>Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Paris</wicri:regionArea></affiliation></author><author><name sortKey="Steinberg, Gregory R" sort="Steinberg, Gregory R" uniqKey="Steinberg G" first="Gregory R." last="Steinberg">Gregory R. Steinberg</name><affiliation><nlm:aff id="Aff9"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 8227</institution-id><institution-id institution-id-type="GRID">grid.25073.33</institution-id><institution>Divisions of Endocrinology and Metabolism, Department of Medicine, and Department of Biochemistry and Biomedical Sciences,</institution><institution>McMaster University,</institution></institution-wrap>Hamilton, ON Canada</nlm:aff><wicri:noCountry code="subfield">ON Canada</wicri:noCountry></affiliation></author><author><name sortKey="Sakamoto, Kei" sort="Sakamoto, Kei" uniqKey="Sakamoto K" first="Kei" last="Sakamoto">Kei Sakamoto</name><affiliation wicri:level="1"><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0397 2876</institution-id><institution-id institution-id-type="GRID">grid.8241.f</institution-id><institution>MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences,</institution><institution>University of Dundee,</institution></institution-wrap>Scotland, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Scotland</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="Aff11"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0066 4948</institution-id><institution-id institution-id-type="GRID">grid.419905.0</institution-id><institution>Present Address: Nestlé Institute of Health Sciences SA,</institution></institution-wrap>Lausanne, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Lausanne</wicri:regionArea></affiliation></author><author><name sortKey="Kemp, Bruce E" sort="Kemp, Bruce E" uniqKey="Kemp B" first="Bruce E." last="Kemp">Bruce E. Kemp</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2179 088X</institution-id><institution-id institution-id-type="GRID">grid.1008.9</institution-id><institution>Protein Chemistry & Metabolism, St Vincent’s Institute of Medical Research,</institution><institution>University of Melbourne,</institution></institution-wrap>Melbourne, VIC Australia</nlm:aff><wicri:noCountry code="subfield">VIC Australia</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2194 1270</institution-id><institution-id institution-id-type="GRID">grid.411958.0</institution-id><institution>Mary MacKillop Institute for Health Research,</institution><institution>Australian Catholic University,</institution></institution-wrap>Melbourne, VIC Australia</nlm:aff><wicri:noCountry code="subfield">VIC Australia</wicri:noCountry></affiliation></author><author><name sortKey="Oakhill, Jonathan S" sort="Oakhill, Jonathan S" uniqKey="Oakhill J" first="Jonathan S." last="Oakhill">Jonathan S. Oakhill</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2179 088X</institution-id><institution-id institution-id-type="GRID">grid.1008.9</institution-id><institution>Metabolic Signalling Laboratory, St Vincent’s Institute of Medical Research,</institution><institution>University of Melbourne,</institution></institution-wrap>Melbourne, VIC Australia</nlm:aff><wicri:noCountry code="subfield">VIC Australia</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2194 1270</institution-id><institution-id institution-id-type="GRID">grid.411958.0</institution-id><institution>Mary MacKillop Institute for Health Research,</institution><institution>Australian Catholic University,</institution></institution-wrap>Melbourne, VIC Australia</nlm:aff><wicri:noCountry code="subfield">VIC Australia</wicri:noCountry></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Hardie, Dg" uniqKey="Hardie D">DG Hardie</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Steinberg, Gr" uniqKey="Steinberg G">GR Steinberg</name></author><author><name sortKey="Kemp, Be" uniqKey="Kemp B">BE Kemp</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Oakhill, Js" uniqKey="Oakhill J">JS Oakhill</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Houde, Vp" uniqKey="Houde V">VP Houde</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Xiao, B" uniqKey="Xiao B">B Xiao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Oakhill, Js" uniqKey="Oakhill J">JS Oakhill</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, L" uniqKey="Chen L">L Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hawley, Sa" uniqKey="Hawley S">SA Hawley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Scott, Jw" uniqKey="Scott J">JW Scott</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Langendorf, Cg" uniqKey="Langendorf C">CG Langendorf</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sanders, Mj" uniqKey="Sanders M">MJ Sanders</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Xiao, B" uniqKey="Xiao B">B Xiao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Scott, Jw" uniqKey="Scott J">JW Scott</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Calabrese, Mf" uniqKey="Calabrese M">MF 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Raijmakers</name></author><author><name sortKey="Lemeer, S" uniqKey="Lemeer S">S Lemeer</name></author><author><name sortKey="Mohammed, S" uniqKey="Mohammed S">S Mohammed</name></author><author><name sortKey="Heck, Aj" uniqKey="Heck A">AJ Heck</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Thingholm, Te" uniqKey="Thingholm T">TE Thingholm</name></author><author><name sortKey="Jorgensen, Tj" uniqKey="Jorgensen T">TJ Jorgensen</name></author><author><name sortKey="Jensen, On" uniqKey="Jensen O">ON Jensen</name></author><author><name sortKey="Larsen, Mr" uniqKey="Larsen M">MR Larsen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tyanova, S" uniqKey="Tyanova S">S Tyanova</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cox, J" uniqKey="Cox J">J Cox</name></author><author><name sortKey="Mann, M" uniqKey="Mann M">M Mann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vizcaino, Ja" uniqKey="Vizcaino J">JA Vizcaíno</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Australie</li><li>France</li><li>Royaume-Uni</li><li>Suisse</li><li>États-Unis</li></country><region><li>Nouvelle-Galles du Sud</li><li>Tennessee</li></region></list><tree><noCountry><name sortKey="Dite, Toby A" sort="Dite, Toby A" uniqKey="Dite T" first="Toby A." last="Dite">Toby A. Dite</name><name sortKey="Galic, Sandra" sort="Galic, Sandra" uniqKey="Galic S" first="Sandra" last="Galic">Sandra Galic</name><name sortKey="Hoque, Ashfaqul" sort="Hoque, Ashfaqul" uniqKey="Hoque A" first="Ashfaqul" last="Hoque">Ashfaqul Hoque</name><name sortKey="Kemp, Bruce E" sort="Kemp, Bruce E" uniqKey="Kemp B" first="Bruce E." last="Kemp">Bruce E. Kemp</name><name sortKey="Langendorf, Christopher G" sort="Langendorf, Christopher G" uniqKey="Langendorf C" first="Christopher G." last="Langendorf">Christopher G. Langendorf</name><name sortKey="Ling, Naomi X Y" sort="Ling, Naomi X Y" uniqKey="Ling N" first="Naomi X. Y." last="Ling">Naomi X. Y. Ling</name><name sortKey="Ngoei, Kevin R W" sort="Ngoei, Kevin R W" uniqKey="Ngoei K" first="Kevin R. W." last="Ngoei">Kevin R. W. Ngoei</name><name sortKey="O Rien, Matthew T" sort="O Rien, Matthew T" uniqKey="O Rien M" first="Matthew T." last="O Rien">Matthew T. O Rien</name><name sortKey="Oakhill, Jonathan S" sort="Oakhill, Jonathan S" uniqKey="Oakhill J" first="Jonathan S." last="Oakhill">Jonathan S. Oakhill</name><name sortKey="Scott, John W" sort="Scott, John W" uniqKey="Scott J" first="John W." last="Scott">John W. Scott</name><name sortKey="Steinberg, Gregory R" sort="Steinberg, Gregory R" uniqKey="Steinberg G" first="Gregory R." last="Steinberg">Gregory R. Steinberg</name></noCountry><country name="Australie"><region name="Nouvelle-Galles du Sud"><name sortKey="Parker, Benjamin L" sort="Parker, Benjamin L" uniqKey="Parker B" first="Benjamin L." last="Parker">Benjamin L. Parker</name></region></country><country name="États-Unis"><region name="Tennessee"><name sortKey="Kundu, Mondira" sort="Kundu, Mondira" uniqKey="Kundu M" first="Mondira" last="Kundu">Mondira Kundu</name></region></country><country name="France"><noRegion><name sortKey="Viollet, Benoit" sort="Viollet, Benoit" uniqKey="Viollet B" first="Benoit" last="Viollet">Benoit Viollet</name></noRegion><name sortKey="Viollet, Benoit" sort="Viollet, Benoit" uniqKey="Viollet B" first="Benoit" last="Viollet">Benoit Viollet</name><name sortKey="Viollet, Benoit" sort="Viollet, Benoit" uniqKey="Viollet B" first="Benoit" last="Viollet">Benoit Viollet</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Sakamoto, Kei" sort="Sakamoto, Kei" uniqKey="Sakamoto K" first="Kei" last="Sakamoto">Kei Sakamoto</name></noRegion></country><country name="Suisse"><noRegion><name sortKey="Sakamoto, Kei" sort="Sakamoto, Kei" uniqKey="Sakamoto K" first="Kei" last="Sakamoto">Kei Sakamoto</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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