{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T07:42:27Z","timestamp":1790840547917,"version":"4.1.0"},"reference-count":60,"publisher":"National Academy of Sciences","issue":"4","license":[{"start":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T00:00:00Z","timestamp":1626912000000},"content-version":"vor","delay-in-days":181,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R01 CA103866"],"award-info":[{"award-number":["R01 CA103866"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R01 CA129105"],"award-info":[{"award-number":["R01 CA129105"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AI047389"],"award-info":[{"award-number":["R01 AI047389"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["2016197106"],"award-info":[{"award-number":["2016197106"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["F30CA210373"],"award-info":[{"award-number":["F30CA210373"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["F31CA228241-01"],"award-info":[{"award-number":["F31CA228241-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["K00CA234839"],"award-info":[{"award-number":["K00CA234839"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["F31CA232355"],"award-info":[{"award-number":["F31CA232355"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2021,1,26]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>The mTORC1 eukaryotic cell growth regulator dynamically responds to changes in environmental nutrient levels. While many upstream regulators are known to modulate mTORC1 activity, the full complement of these is unknown. Here, using a genome-wide FACS-based CRISPR-Cas9 screen, we identify almost all known positive regulators of mTORC1 as well as many others. The results of our screens highlighted the importance of mitochondrial health in the regulation of mTORC1, which led us to investigate how mitochondrial stress impinges on mTORC1 signaling. Ultimately, we found that two kinases, AMPK and HRI, together signal mitochondrial distress to mTORC1. Furthermore, full inhibition of mTORC1 by mitochondrial stress requires the ATF4-dependent up-regulation of two mTORC1 pathway inhibitors, Sestrin2 and Redd1.<\/jats:p>","DOI":"10.1073\/pnas.2022120118","type":"journal-article","created":{"date-parts":[[2021,1,22]],"date-time":"2021-01-22T17:06:10Z","timestamp":1611335170000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":137,"title":["Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction"],"prefix":"10.1073","volume":"118","author":[{"given":"Kendall J.","family":"Condon","sequence":"first","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 02142;"},{"name":"Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139;"},{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142;"},{"name":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142;"},{"name":"Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4587-0777","authenticated-orcid":false,"given":"Jose M.","family":"Orozco","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 02142;"},{"name":"Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139;"},{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142;"},{"name":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142;"},{"name":"Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles H.","family":"Adelmann","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 02142;"},{"name":"Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139;"},{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142;"},{"name":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142;"},{"name":"Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica B.","family":"Spinelli","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 02142;"},{"name":"Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139;"},{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142;"},{"name":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142;"},{"name":"Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4524-8240","authenticated-orcid":false,"given":"Pim W.","family":"van der Helm","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 02142;"},{"name":"Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139;"},{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142;"},{"name":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142;"},{"name":"Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6112-7476","authenticated-orcid":false,"given":"Justin M.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 02142;"},{"name":"Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139;"},{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142;"},{"name":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142;"},{"name":"Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tenzin","family":"Kunchok","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 02142;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1446-7256","authenticated-orcid":false,"given":"David M.","family":"Sabatini","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 02142;"},{"name":"Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139;"},{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142;"},{"name":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142;"},{"name":"Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2021,1,22]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1157535"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11745"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-020-0250-5"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aag1417"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.02.024"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1110003"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb839"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2005.02.053"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.11.049"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.202476899"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(03)00506-2"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.18.7965-7975.2004"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(02)00568-3"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.201800278"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.06.010"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aba5665"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0554-4"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.18129\/B9.bioc.topGO"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1813352116"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.11.015"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03897"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)00108-8"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90193-G"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.50149"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1232044"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature26158"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.AC119.007382"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.269324.115"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad2087"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aab2674"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.10.019"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1063518"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2010.03.014"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C200171200"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00808-5"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1547"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)00929-2"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.10.003"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2008.03.003"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.001286"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx902"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks910"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2078-2"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.04.042"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2076-4"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1256804"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.4161\/cc.4.11.2139"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2008.12.079"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat5314"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201642195"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.49178"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.03.035"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2008.03.013"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.17.10726"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad0489"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1101\/pdb.prot090811"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aac7041"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1101\/pdb.top086892"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1101\/pdb.prot090803"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-018-0113-7"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.pnas.org\/syndication\/doi\/10.1073\/pnas.2022120118","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2022120118","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T06:43:44Z","timestamp":1649832224000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.2022120118"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,22]]},"references-count":60,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,1,26]]}},"alternative-id":["10.1073\/pnas.2022120118"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2022120118","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.10.22.351361","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,22]]},"assertion":[{"value":"2021-01-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2022120118"}}