SAR1B senses leucine levels to regulate mTORC1 signalling
The mTOR complex 1 (mTORC1) controls cell growth in response to amino acid levels 1 . Here we report SAR1B as a leucine sensor that regulates mTORC1 signalling in response to intracellular levels of leucine. Under conditions of leucine deficiency, SAR1B inhibits mTORC1 by physically targeting its ac...
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| Veröffentlicht in: | Nature (London) 2021-08, Vol.596 (7871), p.281-284 |
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| creator | Chen, Jie Ou, Yuhui Luo, Rong Wang, Jie Wang, Dong Guan, Jialiang Li, Yi Xia, Peixue Chen, Peng R. Liu, Ying |
| description | The mTOR complex 1 (mTORC1) controls cell growth in response to amino acid levels
1
. Here we report SAR1B as a leucine sensor that regulates mTORC1 signalling in response to intracellular levels of leucine. Under conditions of leucine deficiency, SAR1B inhibits mTORC1 by physically targeting its activator GATOR2. In conditions of leucine sufficiency, SAR1B binds to leucine, undergoes a conformational change and dissociates from GATOR2, which results in mTORC1 activation. SAR1B–GATOR2–mTORC1 signalling is conserved in nematodes and has a role in the regulation of lifespan. Bioinformatic analysis reveals that SAR1B deficiency correlates with the development of lung cancer. The silencing of SAR1B and its paralogue SAR1A promotes mTORC1-dependent growth of lung tumours in mice. Our results reveal that SAR1B is a conserved leucine sensor that has a potential role in the development of lung cancer.
SAR1B, which is conserved between mammals and nematodes, is a leucine sensor that is involved in regulating mTORC1 signalling and potentially has a role in the development of lung cancer. |
| doi_str_mv | 10.1038/s41586-021-03768-w |
| format | Article |
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1
. Here we report SAR1B as a leucine sensor that regulates mTORC1 signalling in response to intracellular levels of leucine. Under conditions of leucine deficiency, SAR1B inhibits mTORC1 by physically targeting its activator GATOR2. In conditions of leucine sufficiency, SAR1B binds to leucine, undergoes a conformational change and dissociates from GATOR2, which results in mTORC1 activation. SAR1B–GATOR2–mTORC1 signalling is conserved in nematodes and has a role in the regulation of lifespan. Bioinformatic analysis reveals that SAR1B deficiency correlates with the development of lung cancer. The silencing of SAR1B and its paralogue SAR1A promotes mTORC1-dependent growth of lung tumours in mice. Our results reveal that SAR1B is a conserved leucine sensor that has a potential role in the development of lung cancer.
SAR1B, which is conserved between mammals and nematodes, is a leucine sensor that is involved in regulating mTORC1 signalling and potentially has a role in the development of lung cancer.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-021-03768-w</identifier><identifier>PMID: 34290409</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/106 ; 13/89 ; 13/95 ; 631/80 ; 631/80/86/2369 ; 64/11 ; 82 ; 82/29 ; 82/58 ; 82/83 ; 96 ; 96/63 ; Amino acids ; Animals ; Binding sites ; Caenorhabditis elegans - genetics ; Caenorhabditis elegans - metabolism ; Caenorhabditis elegans - physiology ; Caenorhabditis elegans Proteins - genetics ; Caenorhabditis elegans Proteins - metabolism ; Causes of ; Cell growth ; Chemical properties ; Conserved Sequence ; GTP Phosphohydrolases - genetics ; GTP Phosphohydrolases - metabolism ; HEK293 Cells ; Humanities and Social Sciences ; Humans ; Intracellular levels ; Intracellular signalling ; Leucine ; Leucine - deficiency ; Leucine - metabolism ; Life span ; Localization ; Longevity - genetics ; Lung cancer ; Lung diseases ; Lung Neoplasms - genetics ; Lung Neoplasms - metabolism ; Mechanistic Target of Rapamycin Complex 1 - agonists ; Mechanistic Target of Rapamycin Complex 1 - metabolism ; Medical research ; Medicine, Experimental ; Mice ; Monomeric GTP-Binding Proteins - chemistry ; Monomeric GTP-Binding Proteins - deficiency ; Monomeric GTP-Binding Proteins - genetics ; Monomeric GTP-Binding Proteins - metabolism ; multidisciplinary ; Multiprotein Complexes - metabolism ; Nematodes ; Nuclear Proteins - metabolism ; Protein Binding ; Proteins ; Science ; Science (multidisciplinary) ; Sensors ; Signal Transduction ; Signaling ; TOR protein ; Tumor Suppressor Proteins - metabolism ; Tumors ; Xenograft Model Antitumor Assays</subject><ispartof>Nature (London), 2021-08, Vol.596 (7871), p.281-284</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021</rights><rights>2021. The Author(s), under exclusive licence to Springer Nature Limited.</rights><rights>COPYRIGHT 2021 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Aug 12, 2021</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c541t-ca804d1f36cc7537474c4ee0761ddfa5d81a007613972e6bef9afad21a1cb0e33</citedby><cites>FETCH-LOGICAL-c541t-ca804d1f36cc7537474c4ee0761ddfa5d81a007613972e6bef9afad21a1cb0e33</cites><orcidid>0000-0002-7091-7231 ; 0000-0002-0402-7417 ; 0000-0002-3328-026X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41586-021-03768-w$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41586-021-03768-w$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27923,27924,41487,42556,51318</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34290409$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Jie</creatorcontrib><creatorcontrib>Ou, Yuhui</creatorcontrib><creatorcontrib>Luo, Rong</creatorcontrib><creatorcontrib>Wang, Jie</creatorcontrib><creatorcontrib>Wang, Dong</creatorcontrib><creatorcontrib>Guan, Jialiang</creatorcontrib><creatorcontrib>Li, Yi</creatorcontrib><creatorcontrib>Xia, Peixue</creatorcontrib><creatorcontrib>Chen, Peng R.</creatorcontrib><creatorcontrib>Liu, Ying</creatorcontrib><title>SAR1B senses leucine levels to regulate mTORC1 signalling</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>The mTOR complex 1 (mTORC1) controls cell growth in response to amino acid levels
1
. Here we report SAR1B as a leucine sensor that regulates mTORC1 signalling in response to intracellular levels of leucine. Under conditions of leucine deficiency, SAR1B inhibits mTORC1 by physically targeting its activator GATOR2. In conditions of leucine sufficiency, SAR1B binds to leucine, undergoes a conformational change and dissociates from GATOR2, which results in mTORC1 activation. SAR1B–GATOR2–mTORC1 signalling is conserved in nematodes and has a role in the regulation of lifespan. Bioinformatic analysis reveals that SAR1B deficiency correlates with the development of lung cancer. The silencing of SAR1B and its paralogue SAR1A promotes mTORC1-dependent growth of lung tumours in mice. Our results reveal that SAR1B is a conserved leucine sensor that has a potential role in the development of lung cancer.
SAR1B, which is conserved between mammals and nematodes, is a leucine sensor that is involved in regulating mTORC1 signalling and potentially has a role in the development of lung cancer.</description><subject>13/106</subject><subject>13/89</subject><subject>13/95</subject><subject>631/80</subject><subject>631/80/86/2369</subject><subject>64/11</subject><subject>82</subject><subject>82/29</subject><subject>82/58</subject><subject>82/83</subject><subject>96</subject><subject>96/63</subject><subject>Amino acids</subject><subject>Animals</subject><subject>Binding sites</subject><subject>Caenorhabditis elegans - genetics</subject><subject>Caenorhabditis elegans - metabolism</subject><subject>Caenorhabditis elegans - physiology</subject><subject>Caenorhabditis elegans Proteins - genetics</subject><subject>Caenorhabditis elegans Proteins - metabolism</subject><subject>Causes of</subject><subject>Cell growth</subject><subject>Chemical properties</subject><subject>Conserved 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senses leucine levels to regulate mTORC1 signalling</title><author>Chen, Jie ; Ou, Yuhui ; Luo, Rong ; Wang, Jie ; Wang, Dong ; Guan, Jialiang ; Li, Yi ; Xia, Peixue ; Chen, Peng R. ; Liu, Ying</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c541t-ca804d1f36cc7537474c4ee0761ddfa5d81a007613972e6bef9afad21a1cb0e33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>13/106</topic><topic>13/89</topic><topic>13/95</topic><topic>631/80</topic><topic>631/80/86/2369</topic><topic>64/11</topic><topic>82</topic><topic>82/29</topic><topic>82/58</topic><topic>82/83</topic><topic>96</topic><topic>96/63</topic><topic>Amino acids</topic><topic>Animals</topic><topic>Binding sites</topic><topic>Caenorhabditis elegans - genetics</topic><topic>Caenorhabditis elegans - metabolism</topic><topic>Caenorhabditis elegans - physiology</topic><topic>Caenorhabditis elegans Proteins - 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Jialiang</au><au>Li, Yi</au><au>Xia, Peixue</au><au>Chen, Peng R.</au><au>Liu, Ying</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SAR1B senses leucine levels to regulate mTORC1 signalling</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2021-08-12</date><risdate>2021</risdate><volume>596</volume><issue>7871</issue><spage>281</spage><epage>284</epage><pages>281-284</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>The mTOR complex 1 (mTORC1) controls cell growth in response to amino acid levels
1
. Here we report SAR1B as a leucine sensor that regulates mTORC1 signalling in response to intracellular levels of leucine. Under conditions of leucine deficiency, SAR1B inhibits mTORC1 by physically targeting its activator GATOR2. In conditions of leucine sufficiency, SAR1B binds to leucine, undergoes a conformational change and dissociates from GATOR2, which results in mTORC1 activation. SAR1B–GATOR2–mTORC1 signalling is conserved in nematodes and has a role in the regulation of lifespan. Bioinformatic analysis reveals that SAR1B deficiency correlates with the development of lung cancer. The silencing of SAR1B and its paralogue SAR1A promotes mTORC1-dependent growth of lung tumours in mice. Our results reveal that SAR1B is a conserved leucine sensor that has a potential role in the development of lung cancer.
SAR1B, which is conserved between mammals and nematodes, is a leucine sensor that is involved in regulating mTORC1 signalling and potentially has a role in the development of lung cancer.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34290409</pmid><doi>10.1038/s41586-021-03768-w</doi><tpages>4</tpages><orcidid>https://orcid.org/0000-0002-7091-7231</orcidid><orcidid>https://orcid.org/0000-0002-0402-7417</orcidid><orcidid>https://orcid.org/0000-0002-3328-026X</orcidid></addata></record> |
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| recordid | cdi_proquest_miscellaneous_2554351009 |
| source | MEDLINE; Nature Journals Online; SpringerLink Journals - AutoHoldings |
| subjects | 13/106 13/89 13/95 631/80 631/80/86/2369 64/11 82 82/29 82/58 82/83 96 96/63 Amino acids Animals Binding sites Caenorhabditis elegans - genetics Caenorhabditis elegans - metabolism Caenorhabditis elegans - physiology Caenorhabditis elegans Proteins - genetics Caenorhabditis elegans Proteins - metabolism Causes of Cell growth Chemical properties Conserved Sequence GTP Phosphohydrolases - genetics GTP Phosphohydrolases - metabolism HEK293 Cells Humanities and Social Sciences Humans Intracellular levels Intracellular signalling Leucine Leucine - deficiency Leucine - metabolism Life span Localization Longevity - genetics Lung cancer Lung diseases Lung Neoplasms - genetics Lung Neoplasms - metabolism Mechanistic Target of Rapamycin Complex 1 - agonists Mechanistic Target of Rapamycin Complex 1 - metabolism Medical research Medicine, Experimental Mice Monomeric GTP-Binding Proteins - chemistry Monomeric GTP-Binding Proteins - deficiency Monomeric GTP-Binding Proteins - genetics Monomeric GTP-Binding Proteins - metabolism multidisciplinary Multiprotein Complexes - metabolism Nematodes Nuclear Proteins - metabolism Protein Binding Proteins Science Science (multidisciplinary) Sensors Signal Transduction Signaling TOR protein Tumor Suppressor Proteins - metabolism Tumors Xenograft Model Antitumor Assays |
| title | SAR1B senses leucine levels to regulate mTORC1 signalling |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-11T18%3A25%3A32IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=SAR1B%20senses%20leucine%20levels%20to%20regulate%20mTORC1%20signalling&rft.jtitle=Nature%20(London)&rft.au=Chen,%20Jie&rft.date=2021-08-12&rft.volume=596&rft.issue=7871&rft.spage=281&rft.epage=284&rft.pages=281-284&rft.issn=0028-0836&rft.eissn=1476-4687&rft_id=info:doi/10.1038/s41586-021-03768-w&rft_dat=%3Cgale_proqu%3EA671657909%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2561108904&rft_id=info:pmid/34290409&rft_galeid=A671657909&rfr_iscdi=true |