Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy
Adenosine monophosphate-activated protein kinase (AMPK) is a conserved sensor of intracellular energy activated in response to low nutrient availability and environmental stress. In a screen for conserved substrates of AMPK, we identified ULK1 and ULK2, mammalian orthologs of the yeast protein kinas...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2011-01, Vol.331 (6016), p.456-461 |
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| creator | Egan, Daniel F Shackelford, David B Mihaylova, Maria M Gelino, Sara Kohnz, Rebecca A Mair, William Vasquez, Debbie S Joshi, Aashish Gwinn, Dana M Taylor, Rebecca Asara, John M Fitzpatrick, James Dillin, Andrew Viollet, Benoit Kundu, Mondira Hansen, Malene Shaw, Reuben J |
| description | Adenosine monophosphate-activated protein kinase (AMPK) is a conserved sensor of intracellular energy activated in response to low nutrient availability and environmental stress. In a screen for conserved substrates of AMPK, we identified ULK1 and ULK2, mammalian orthologs of the yeast protein kinase Atg1, which is required for autophagy. Genetic analysis of AMPK or ULK1 in mammalian liver and Caenorhabditis elegans revealed a requirement for these kinases in autophagy. In mammals, loss of AMPK or ULK1 resulted in aberrant accumulation of the autophagy adaptor p62 and defective mitophagy. Reconstitution of ULK1-deficient cells with a mutant ULK1 that cannot be phosphorylated by AMPK revealed that such phosphorylation is required for mitochondrial homeostasis and cell survival during starvation. These findings uncover a conserved biochemical mechanism coupling nutrient status with autophagy and cell survival. |
| doi_str_mv | 10.1126/science.1196371 |
| format | Article |
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In a screen for conserved substrates of AMPK, we identified ULK1 and ULK2, mammalian orthologs of the yeast protein kinase Atg1, which is required for autophagy. Genetic analysis of AMPK or ULK1 in mammalian liver and Caenorhabditis elegans revealed a requirement for these kinases in autophagy. In mammals, loss of AMPK or ULK1 resulted in aberrant accumulation of the autophagy adaptor p62 and defective mitophagy. Reconstitution of ULK1-deficient cells with a mutant ULK1 that cannot be phosphorylated by AMPK revealed that such phosphorylation is required for mitochondrial homeostasis and cell survival during starvation. These findings uncover a conserved biochemical mechanism coupling nutrient status with autophagy and cell survival.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.1196371</identifier><identifier>PMID: 21205641</identifier><identifier>CODEN: SCIEAS</identifier><language>eng</language><publisher>Washington, DC: American Association for the Advancement of Science</publisher><subject>Adaptor Proteins, Signal Transducing - metabolism ; Adenosines ; AMP-Activated Protein Kinases - metabolism ; Animals ; Autophagy ; Autophagy-Related Protein-1 Homolog ; Biological and medical sciences ; Birds of prey ; Caenorhabditis elegans - metabolism ; Caenorhabditis elegans Proteins - genetics ; Caenorhabditis elegans Proteins - metabolism ; Cell Line ; Cell Line, Tumor ; Cell lines ; Cell Survival ; Classical genetics, quantitative genetics, hybrids ; Complementary DNA ; Energy Metabolism ; Fundamental and applied biological sciences. 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Biological and molecular evolution ; Hepatocytes ; Hepatocytes - metabolism ; Homeostasis ; Humans ; Insulin - metabolism ; Intracellular Signaling Peptides and Proteins - chemistry ; Intracellular Signaling Peptides and Proteins - genetics ; Intracellular Signaling Peptides and Proteins - metabolism ; Kinases ; Liver ; Liver - metabolism ; Medical research ; Metformin - pharmacology ; Mice ; Mitochondria ; Mitochondria, Liver - metabolism ; Mitochondria, Liver - ultrastructure ; Nutrients ; Phenformin - pharmacology ; Phosphorylation ; Protein Serine-Threonine Kinases - chemistry ; Protein Serine-Threonine Kinases - genetics ; Protein Serine-Threonine Kinases - metabolism ; Proteins ; Sequestosome-1 Protein ; Signal Transduction ; Starvation ; Survival ; Transcription Factor TFIIH ; Transcription Factors - metabolism ; Vehicles ; Yeast</subject><ispartof>Science (American Association for the Advancement of Science), 2011-01, Vol.331 (6016), p.456-461</ispartof><rights>Copyright © 2011 American Association for the Advancement of Science</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011, American Association for the Advancement of Science</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c593t-e625bc81540ecd2ead968979029b5d3cb7815d5fb1365cc90b41db10dedafaad3</citedby><cites>FETCH-LOGICAL-c593t-e625bc81540ecd2ead968979029b5d3cb7815d5fb1365cc90b41db10dedafaad3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/25790181$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/25790181$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,777,781,800,882,2871,2872,27905,27906,57998,58231</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23810947$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21205641$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Egan, Daniel F</creatorcontrib><creatorcontrib>Shackelford, David B</creatorcontrib><creatorcontrib>Mihaylova, Maria M</creatorcontrib><creatorcontrib>Gelino, Sara</creatorcontrib><creatorcontrib>Kohnz, Rebecca A</creatorcontrib><creatorcontrib>Mair, William</creatorcontrib><creatorcontrib>Vasquez, Debbie S</creatorcontrib><creatorcontrib>Joshi, Aashish</creatorcontrib><creatorcontrib>Gwinn, Dana M</creatorcontrib><creatorcontrib>Taylor, Rebecca</creatorcontrib><creatorcontrib>Asara, John M</creatorcontrib><creatorcontrib>Fitzpatrick, James</creatorcontrib><creatorcontrib>Dillin, Andrew</creatorcontrib><creatorcontrib>Viollet, Benoit</creatorcontrib><creatorcontrib>Kundu, Mondira</creatorcontrib><creatorcontrib>Hansen, Malene</creatorcontrib><creatorcontrib>Shaw, Reuben J</creatorcontrib><title>Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>Adenosine monophosphate-activated protein kinase (AMPK) is a conserved sensor of intracellular energy activated in response to low nutrient availability and environmental stress. In a screen for conserved substrates of AMPK, we identified ULK1 and ULK2, mammalian orthologs of the yeast protein kinase Atg1, which is required for autophagy. Genetic analysis of AMPK or ULK1 in mammalian liver and Caenorhabditis elegans revealed a requirement for these kinases in autophagy. In mammals, loss of AMPK or ULK1 resulted in aberrant accumulation of the autophagy adaptor p62 and defective mitophagy. Reconstitution of ULK1-deficient cells with a mutant ULK1 that cannot be phosphorylated by AMPK revealed that such phosphorylation is required for mitochondrial homeostasis and cell survival during starvation. These findings uncover a conserved biochemical mechanism coupling nutrient status with autophagy and cell survival.</description><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Adenosines</subject><subject>AMP-Activated Protein Kinases - metabolism</subject><subject>Animals</subject><subject>Autophagy</subject><subject>Autophagy-Related Protein-1 Homolog</subject><subject>Biological and medical sciences</subject><subject>Birds of prey</subject><subject>Caenorhabditis elegans - metabolism</subject><subject>Caenorhabditis elegans Proteins - genetics</subject><subject>Caenorhabditis elegans Proteins - metabolism</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>Cell lines</subject><subject>Cell Survival</subject><subject>Classical genetics, quantitative genetics, hybrids</subject><subject>Complementary DNA</subject><subject>Energy Metabolism</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Genetics of eukaryotes. Biological and molecular evolution</subject><subject>Hepatocytes</subject><subject>Hepatocytes - metabolism</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Insulin - metabolism</subject><subject>Intracellular Signaling Peptides and Proteins - chemistry</subject><subject>Intracellular Signaling Peptides and Proteins - genetics</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Kinases</subject><subject>Liver</subject><subject>Liver - metabolism</subject><subject>Medical research</subject><subject>Metformin - pharmacology</subject><subject>Mice</subject><subject>Mitochondria</subject><subject>Mitochondria, Liver - metabolism</subject><subject>Mitochondria, Liver - ultrastructure</subject><subject>Nutrients</subject><subject>Phenformin - pharmacology</subject><subject>Phosphorylation</subject><subject>Protein Serine-Threonine Kinases - chemistry</subject><subject>Protein Serine-Threonine Kinases - genetics</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Proteins</subject><subject>Sequestosome-1 Protein</subject><subject>Signal Transduction</subject><subject>Starvation</subject><subject>Survival</subject><subject>Transcription Factor TFIIH</subject><subject>Transcription Factors - metabolism</subject><subject>Vehicles</subject><subject>Yeast</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFks9v0zAcxS0EYqVw5gRYSBNwCPOPOIkvSFU1BlonKm09W47tJK5Su7PdSf3v8dRuAy6cLOt9_Pz8fQbgLUZfMSbVWVTWOGXyhle0xs_ABCPOCk4QfQ4mCNGqaFDNTsCrGNcIZY3Tl-CEYIJYVeIJ0MvBx-3gw36UyXoHfQdXi0sMPw-zmwv8BbZ7OLtaFjOV7J1MRsNl8MlYBy-tk9HAuXfOqBThuTOh38Nr46J1PUweXtnkt4Ps96_Bi06O0bw5rlOw-n5-M_9RLH5d_JzPFoXKsVJhKsJa1WBWIqM0MVLzquE1R4S3TFPV1lnTrGsxrZhSHLUl1i1G2mjZSanpFHw7-G537cZoZVwKchTbYDcy7IWXVvytODuI3t8JiiiqqjIbfDoaBH-7MzGJjY3KjKN0xu-i4KjmlGBK_0s2ZUMJKinJ5Md_yLXfBZfnIJo618Bwvn0Kzg6QCj7GYLrH0BiJ-6bFsWlxbDqfeP_nWx_5h2ozcHoEZFRy7IJ0ysYnjjb5q5R15t4duHVMPjzpLA8eN_c-Hw56J72Qfcgeq2uCcmrMKWOc0d9VeMUk</recordid><startdate>20110128</startdate><enddate>20110128</enddate><creator>Egan, Daniel F</creator><creator>Shackelford, David B</creator><creator>Mihaylova, Maria M</creator><creator>Gelino, Sara</creator><creator>Kohnz, Rebecca A</creator><creator>Mair, William</creator><creator>Vasquez, Debbie S</creator><creator>Joshi, Aashish</creator><creator>Gwinn, Dana M</creator><creator>Taylor, Rebecca</creator><creator>Asara, John M</creator><creator>Fitzpatrick, James</creator><creator>Dillin, Andrew</creator><creator>Viollet, Benoit</creator><creator>Kundu, Mondira</creator><creator>Hansen, Malene</creator><creator>Shaw, Reuben J</creator><general>American Association for the Advancement of Science</general><general>The American Association for the Advancement of Science</general><scope>FBQ</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QF</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QQ</scope><scope>7QR</scope><scope>7SC</scope><scope>7SE</scope><scope>7SN</scope><scope>7SP</scope><scope>7SR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7TK</scope><scope>7TM</scope><scope>7U5</scope><scope>7U9</scope><scope>8BQ</scope><scope>8FD</scope><scope>C1K</scope><scope>F28</scope><scope>FR3</scope><scope>H8D</scope><scope>H8G</scope><scope>H94</scope><scope>JG9</scope><scope>JQ2</scope><scope>K9.</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20110128</creationdate><title>Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy</title><author>Egan, Daniel F ; Shackelford, David B ; Mihaylova, Maria M ; Gelino, Sara ; Kohnz, Rebecca A ; Mair, William ; Vasquez, Debbie S ; Joshi, Aashish ; Gwinn, Dana M ; Taylor, Rebecca ; Asara, John M ; Fitzpatrick, James ; Dillin, Andrew ; Viollet, Benoit ; Kundu, Mondira ; Hansen, Malene ; Shaw, Reuben J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c593t-e625bc81540ecd2ead968979029b5d3cb7815d5fb1365cc90b41db10dedafaad3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Adenosines</topic><topic>AMP-Activated Protein Kinases - metabolism</topic><topic>Animals</topic><topic>Autophagy</topic><topic>Autophagy-Related Protein-1 Homolog</topic><topic>Biological and medical sciences</topic><topic>Birds of prey</topic><topic>Caenorhabditis elegans - metabolism</topic><topic>Caenorhabditis elegans Proteins - genetics</topic><topic>Caenorhabditis elegans Proteins - metabolism</topic><topic>Cell Line</topic><topic>Cell Line, Tumor</topic><topic>Cell lines</topic><topic>Cell Survival</topic><topic>Classical genetics, quantitative genetics, hybrids</topic><topic>Complementary DNA</topic><topic>Energy Metabolism</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Genetics of eukaryotes. Biological and molecular evolution</topic><topic>Hepatocytes</topic><topic>Hepatocytes - metabolism</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Insulin - metabolism</topic><topic>Intracellular Signaling Peptides and Proteins - chemistry</topic><topic>Intracellular Signaling Peptides and Proteins - genetics</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>Kinases</topic><topic>Liver</topic><topic>Liver - metabolism</topic><topic>Medical research</topic><topic>Metformin - pharmacology</topic><topic>Mice</topic><topic>Mitochondria</topic><topic>Mitochondria, Liver - metabolism</topic><topic>Mitochondria, Liver - ultrastructure</topic><topic>Nutrients</topic><topic>Phenformin - pharmacology</topic><topic>Phosphorylation</topic><topic>Protein Serine-Threonine Kinases - chemistry</topic><topic>Protein Serine-Threonine Kinases - genetics</topic><topic>Protein Serine-Threonine Kinases - metabolism</topic><topic>Proteins</topic><topic>Sequestosome-1 Protein</topic><topic>Signal Transduction</topic><topic>Starvation</topic><topic>Survival</topic><topic>Transcription Factor TFIIH</topic><topic>Transcription Factors - 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In a screen for conserved substrates of AMPK, we identified ULK1 and ULK2, mammalian orthologs of the yeast protein kinase Atg1, which is required for autophagy. Genetic analysis of AMPK or ULK1 in mammalian liver and Caenorhabditis elegans revealed a requirement for these kinases in autophagy. In mammals, loss of AMPK or ULK1 resulted in aberrant accumulation of the autophagy adaptor p62 and defective mitophagy. Reconstitution of ULK1-deficient cells with a mutant ULK1 that cannot be phosphorylated by AMPK revealed that such phosphorylation is required for mitochondrial homeostasis and cell survival during starvation. These findings uncover a conserved biochemical mechanism coupling nutrient status with autophagy and cell survival.</abstract><cop>Washington, DC</cop><pub>American Association for the Advancement of Science</pub><pmid>21205641</pmid><doi>10.1126/science.1196371</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Science (American Association for the Advancement of Science), 2011-01, Vol.331 (6016), p.456-461 |
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| language | eng |
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| source | MEDLINE; American Association for the Advancement of Science; Jstor Complete Legacy |
| subjects | Adaptor Proteins, Signal Transducing - metabolism Adenosines AMP-Activated Protein Kinases - metabolism Animals Autophagy Autophagy-Related Protein-1 Homolog Biological and medical sciences Birds of prey Caenorhabditis elegans - metabolism Caenorhabditis elegans Proteins - genetics Caenorhabditis elegans Proteins - metabolism Cell Line Cell Line, Tumor Cell lines Cell Survival Classical genetics, quantitative genetics, hybrids Complementary DNA Energy Metabolism Fundamental and applied biological sciences. Psychology Genetics of eukaryotes. Biological and molecular evolution Hepatocytes Hepatocytes - metabolism Homeostasis Humans Insulin - metabolism Intracellular Signaling Peptides and Proteins - chemistry Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism Kinases Liver Liver - metabolism Medical research Metformin - pharmacology Mice Mitochondria Mitochondria, Liver - metabolism Mitochondria, Liver - ultrastructure Nutrients Phenformin - pharmacology Phosphorylation Protein Serine-Threonine Kinases - chemistry Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - metabolism Proteins Sequestosome-1 Protein Signal Transduction Starvation Survival Transcription Factor TFIIH Transcription Factors - metabolism Vehicles Yeast |
| title | Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy |
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