GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2
Mammalian cells possess two amino acid-sensing kinases: general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1). Their combined effects orchestrate cellular adaptation to amino acid levels, but how their activities are coordinated remains poorly understood. H...
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| Veröffentlicht in: | Genes & development 2015-11, Vol.29 (22), p.2331-2336 |
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| creator | Ye, Jiangbin Palm, Wilhelm Peng, Min King, Bryan Lindsten, Tullia Li, Ming O Koumenis, Constantinos Thompson, Craig B |
| description | Mammalian cells possess two amino acid-sensing kinases: general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1). Their combined effects orchestrate cellular adaptation to amino acid levels, but how their activities are coordinated remains poorly understood. Here, we demonstrate an important link between GCN2 and mTORC1 signaling. Upon deprivation of various amino acids, activated GCN2 up-regulates ATF4 to induce expression of the stress response protein Sestrin2, which is required to sustain repression of mTORC1 by blocking its lysosomal localization. Moreover, Sestrin2 induction is necessary for cell survival during glutamine deprivation, indicating that Sestrin2 is a critical effector of GCN2 signaling that regulates amino acid homeostasis through mTORC1 suppression. |
| doi_str_mv | 10.1101/gad.269324.115 |
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Their combined effects orchestrate cellular adaptation to amino acid levels, but how their activities are coordinated remains poorly understood. Here, we demonstrate an important link between GCN2 and mTORC1 signaling. Upon deprivation of various amino acids, activated GCN2 up-regulates ATF4 to induce expression of the stress response protein Sestrin2, which is required to sustain repression of mTORC1 by blocking its lysosomal localization. Moreover, Sestrin2 induction is necessary for cell survival during glutamine deprivation, indicating that Sestrin2 is a critical effector of GCN2 signaling that regulates amino acid homeostasis through mTORC1 suppression.</description><identifier>ISSN: 0890-9369</identifier><identifier>EISSN: 1549-5477</identifier><identifier>DOI: 10.1101/gad.269324.115</identifier><identifier>PMID: 26543160</identifier><language>eng</language><publisher>United States: Cold Spring Harbor Laboratory Press</publisher><subject>Activating Transcription Factor 4 - genetics ; Activating Transcription Factor 4 - metabolism ; Amino Acids - metabolism ; Animals ; Cell Line ; Cell Line, Tumor ; Cell Survival - genetics ; Gene Expression Regulation ; HEK293 Cells ; Humans ; Lysosomes - metabolism ; Mechanistic Target of Rapamycin Complex 1 ; Mice ; Multiprotein Complexes - metabolism ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Protein-Serine-Threonine Kinases - metabolism ; Research Communication ; Signal Transduction ; TOR Serine-Threonine Kinases - metabolism</subject><ispartof>Genes & development, 2015-11, Vol.29 (22), p.2331-2336</ispartof><rights>2015 Ye et al.; Published by Cold Spring Harbor Laboratory Press.</rights><rights>2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c489t-29b4b2b9fea0c33ad215183d4af00b50189d14f78e323b1ef7b3e3f9bd71ebbc3</citedby><cites>FETCH-LOGICAL-c489t-29b4b2b9fea0c33ad215183d4af00b50189d14f78e323b1ef7b3e3f9bd71ebbc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691887/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691887/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,886,27929,27930,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26543160$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ye, Jiangbin</creatorcontrib><creatorcontrib>Palm, Wilhelm</creatorcontrib><creatorcontrib>Peng, Min</creatorcontrib><creatorcontrib>King, Bryan</creatorcontrib><creatorcontrib>Lindsten, Tullia</creatorcontrib><creatorcontrib>Li, Ming O</creatorcontrib><creatorcontrib>Koumenis, Constantinos</creatorcontrib><creatorcontrib>Thompson, Craig B</creatorcontrib><title>GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2</title><title>Genes & development</title><addtitle>Genes Dev</addtitle><description>Mammalian cells possess two amino acid-sensing kinases: general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1). 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Moreover, Sestrin2 induction is necessary for cell survival during glutamine deprivation, indicating that Sestrin2 is a critical effector of GCN2 signaling that regulates amino acid homeostasis through mTORC1 suppression.</description><subject>Activating Transcription Factor 4 - genetics</subject><subject>Activating Transcription Factor 4 - metabolism</subject><subject>Amino Acids - metabolism</subject><subject>Animals</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - genetics</subject><subject>Gene Expression Regulation</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Lysosomes - metabolism</subject><subject>Mechanistic Target of Rapamycin Complex 1</subject><subject>Mice</subject><subject>Multiprotein Complexes - metabolism</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - metabolism</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Research Communication</subject><subject>Signal Transduction</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><issn>0890-9369</issn><issn>1549-5477</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNUU1LxDAUDKLounr1KD166ZqXpGlzEWTRVVgUv84hadI1sk1r0y7svzfL6qI3L-8xzLxhHoPQGeAJAIbLhTITwgUlLOJsD40gYyLNWJ7voxEuBE4F5eIIHYfwgTHmmPNDdER4xihwPEJPs-kDScIQeuV8SOrXx-cpRNy2nQ3BNT4Z2jhU7XyTqNKZxNi2cyvVbzi9Tpw3Q-n8Inmxoe-cJyfooFLLYE-_9xi93d68Tu_S-ePsfno9T0tWiD4lQjNNtKiswiWlyhDIoKCGqQpjnWEohAFW5YWlhGqwVa6ppZXQJgerdUnH6Grr2w66tqa0vu_UUsZwterWslFO_mW8e5eLZiUZF1AUeTS4-Dboms8hppe1C6VdLpW3zRAk5DnnmQDC_iGlGY054xyjyVZadk0Ina12iQDLTWUyVia3lUW8OTj__cdO_tMR_QIzkpMB</recordid><startdate>20151115</startdate><enddate>20151115</enddate><creator>Ye, Jiangbin</creator><creator>Palm, Wilhelm</creator><creator>Peng, Min</creator><creator>King, Bryan</creator><creator>Lindsten, Tullia</creator><creator>Li, Ming O</creator><creator>Koumenis, Constantinos</creator><creator>Thompson, Craig B</creator><general>Cold Spring Harbor Laboratory Press</general><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>7X8</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20151115</creationdate><title>GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2</title><author>Ye, Jiangbin ; Palm, Wilhelm ; Peng, Min ; King, Bryan ; Lindsten, Tullia ; Li, Ming O ; Koumenis, Constantinos ; Thompson, Craig B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c489t-29b4b2b9fea0c33ad215183d4af00b50189d14f78e323b1ef7b3e3f9bd71ebbc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Activating Transcription Factor 4 - genetics</topic><topic>Activating Transcription Factor 4 - metabolism</topic><topic>Amino Acids - metabolism</topic><topic>Animals</topic><topic>Cell Line</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival - genetics</topic><topic>Gene Expression Regulation</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Lysosomes - metabolism</topic><topic>Mechanistic Target of Rapamycin Complex 1</topic><topic>Mice</topic><topic>Multiprotein Complexes - metabolism</topic><topic>Nuclear Proteins - genetics</topic><topic>Nuclear Proteins - metabolism</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Research Communication</topic><topic>Signal Transduction</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ye, Jiangbin</creatorcontrib><creatorcontrib>Palm, Wilhelm</creatorcontrib><creatorcontrib>Peng, Min</creatorcontrib><creatorcontrib>King, Bryan</creatorcontrib><creatorcontrib>Lindsten, Tullia</creatorcontrib><creatorcontrib>Li, Ming O</creatorcontrib><creatorcontrib>Koumenis, Constantinos</creatorcontrib><creatorcontrib>Thompson, Craig B</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genes & development</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ye, Jiangbin</au><au>Palm, Wilhelm</au><au>Peng, Min</au><au>King, Bryan</au><au>Lindsten, Tullia</au><au>Li, Ming O</au><au>Koumenis, Constantinos</au><au>Thompson, Craig B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2</atitle><jtitle>Genes & development</jtitle><addtitle>Genes Dev</addtitle><date>2015-11-15</date><risdate>2015</risdate><volume>29</volume><issue>22</issue><spage>2331</spage><epage>2336</epage><pages>2331-2336</pages><issn>0890-9369</issn><eissn>1549-5477</eissn><abstract>Mammalian cells possess two amino acid-sensing kinases: general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1). Their combined effects orchestrate cellular adaptation to amino acid levels, but how their activities are coordinated remains poorly understood. Here, we demonstrate an important link between GCN2 and mTORC1 signaling. Upon deprivation of various amino acids, activated GCN2 up-regulates ATF4 to induce expression of the stress response protein Sestrin2, which is required to sustain repression of mTORC1 by blocking its lysosomal localization. Moreover, Sestrin2 induction is necessary for cell survival during glutamine deprivation, indicating that Sestrin2 is a critical effector of GCN2 signaling that regulates amino acid homeostasis through mTORC1 suppression.</abstract><cop>United States</cop><pub>Cold Spring Harbor Laboratory Press</pub><pmid>26543160</pmid><doi>10.1101/gad.269324.115</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Activating Transcription Factor 4 - genetics Activating Transcription Factor 4 - metabolism Amino Acids - metabolism Animals Cell Line Cell Line, Tumor Cell Survival - genetics Gene Expression Regulation HEK293 Cells Humans Lysosomes - metabolism Mechanistic Target of Rapamycin Complex 1 Mice Multiprotein Complexes - metabolism Nuclear Proteins - genetics Nuclear Proteins - metabolism Protein-Serine-Threonine Kinases - metabolism Research Communication Signal Transduction TOR Serine-Threonine Kinases - metabolism |
| title | GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2 |
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