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Award","award":["DGECR-2018-00093"],"award-info":[{"award-number":["DGECR-2018-00093"]}]},{"name":"institutional funding from the CERVO Brain Research Centre and a Tuberous Sclerosis Complex (TSC) Alliance Biorepository Seed grant","award":["RGPIN-2020-06376"],"award-info":[{"award-number":["RGPIN-2020-06376"]}]},{"name":"institutional funding from the CERVO Brain Research Centre and a Tuberous Sclerosis Complex (TSC) Alliance Biorepository Seed grant","award":["DGECR-2020-00060"],"award-info":[{"award-number":["DGECR-2020-00060"]}]},{"name":"institutional funding from the CERVO Brain Research Centre and a Tuberous Sclerosis Complex (TSC) Alliance Biorepository Seed grant","award":["RGPIN-2018-06227"],"award-info":[{"award-number":["RGPIN-2018-06227"]}]},{"name":"institutional funding from the CERVO Brain Research Centre and a Tuberous Sclerosis Complex (TSC) Alliance Biorepository Seed grant","award":["DGECR-2018-00093"],"award-info":[{"award-number":["DGECR-2018-00093"]}]},{"name":"a graduate scholarship from the CERVO Foundation","award":["RGPIN-2020-06376"],"award-info":[{"award-number":["RGPIN-2020-06376"]}]},{"name":"a graduate scholarship from the CERVO Foundation","award":["DGECR-2020-00060"],"award-info":[{"award-number":["DGECR-2020-00060"]}]},{"name":"a graduate scholarship from the CERVO Foundation","award":["RGPIN-2018-06227"],"award-info":[{"award-number":["RGPIN-2018-06227"]}]},{"name":"a graduate scholarship from the CERVO Foundation","award":["DGECR-2018-00093"],"award-info":[{"award-number":["DGECR-2018-00093"]}]},{"name":"the Natural Sciences and Engineering Research Council of Canada Undergraduate Research Student Award (URSA) scholarship","award":["RGPIN-2020-06376"],"award-info":[{"award-number":["RGPIN-2020-06376"]}]},{"name":"the Natural Sciences and Engineering Research Council of Canada Undergraduate Research Student Award (URSA) scholarship","award":["DGECR-2020-00060"],"award-info":[{"award-number":["DGECR-2020-00060"]}]},{"name":"the Natural Sciences and Engineering Research Council of Canada Undergraduate Research Student Award (URSA) scholarship","award":["RGPIN-2018-06227"],"award-info":[{"award-number":["RGPIN-2018-06227"]}]},{"name":"the Natural Sciences and Engineering Research Council of Canada Undergraduate Research Student Award (URSA) scholarship","award":["DGECR-2018-00093"],"award-info":[{"award-number":["DGECR-2018-00093"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>GATOR1 (GAP Activity TOward Rag 1) is an evolutionarily conserved GTPase-activating protein complex that controls the activity of mTORC1 (mammalian Target Of Rapamycin Complex 1) in response to amino acid availability in cells. Genetic mutations in the GATOR1 subunits, NPRL2 (nitrogen permease regulator-like 2), NPRL3 (nitrogen permease regulator-like 3), and DEPDC5 (DEP domain containing 5), have been associated with epilepsy in humans; however, the specific effects of these mutations on GATOR1 function and mTORC1 regulation are not well understood. Herein, we report that epilepsy-linked mutations in the NPRL2 subunit of GATOR1, NPRL2-L105P, -T110S, and -D214H, increase basal mTORC1 signal transduction in cells. Notably, we show that NPRL2-L105P is a loss-of-function mutation that disrupts protein interactions with NPRL3 and DEPDC5, impairing GATOR1 complex assembly and resulting in high mTORC1 activity even under conditions of amino acid deprivation. Furthermore, our studies reveal that the GATOR1 complex is necessary for the rapid and robust inhibition of mTORC1 in response to growth factor withdrawal or pharmacological inhibition of phosphatidylinositol-3 kinase (PI3K). In the absence of the GATOR1 complex, cells are refractory to PI3K-dependent inhibition of mTORC1, permitting sustained translation and restricting the nuclear localization of TFEB, a transcription factor regulated by mTORC1. Collectively, our results show that epilepsy-linked mutations in NPRL2 can block GATOR1 complex assembly and restrict the appropriate regulation of mTORC1 by canonical PI3K-dependent growth factor signaling in the presence or absence of amino acids.<\/jats:p>","DOI":"10.3390\/ijms25042068","type":"journal-article","created":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T09:00:02Z","timestamp":1707382802000},"page":"2068","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["GATOR1 Mutations Impair PI3 Kinase-Dependent Growth Factor Signaling Regulation of mTORC1"],"prefix":"10.3390","volume":"25","author":[{"given":"Ma\u00e9line","family":"Muller","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Neuroscience, CERVO Brain Research Centre, Universit\u00e9 Laval, Quebec City, QC G1J 2G3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmine","family":"B\u00e9langer","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neuroscience, CERVO Brain Research Centre, Universit\u00e9 Laval, Quebec City, QC G1J 2G3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imane","family":"Hadj-Aissa","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neuroscience, CERVO Brain Research Centre, Universit\u00e9 Laval, Quebec City, QC G1J 2G3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conghao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neuroscience, CERVO Brain Research Centre, Universit\u00e9 Laval, Quebec City, QC G1J 2G3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9839-0611","authenticated-orcid":false,"given":"Chantelle F.","family":"Sephton","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neuroscience, CERVO Brain Research Centre, Universit\u00e9 Laval, Quebec City, QC G1J 2G3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7965-8870","authenticated-orcid":false,"given":"Paul A.","family":"Dutchak","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neuroscience, CERVO Brain Research Centre, Universit\u00e9 Laval, Quebec City, QC G1J 2G3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1038\/s41436-018-0060-2","article-title":"The landscape of epilepsy-related GATOR1 variants","volume":"21","author":"Baldassari","year":"2019","journal-title":"Genet. 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