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dc.contributor.authorMunson, Michael J.
dc.contributor.authorAllen, George F. G.
dc.contributor.authorToth, Rachel
dc.contributor.authorCampbell, David G.
dc.contributor.authorLucocq, John M.
dc.contributor.authorGanley, Ian G.
dc.date.accessioned2015-07-24T14:40:02Z
dc.date.available2015-07-24T14:40:02Z
dc.date.issued2015-09-02
dc.identifier.citationMunson , M J , Allen , G F G , Toth , R , Campbell , D G , Lucocq , J M & Ganley , I G 2015 , ' mTOR activates the VPS34-UVRAG complex to regulate autolysosomal tubulation and cell survival ' , EMBO Journal , vol. 34 , no. 17 , pp. 2272-2290 . https://doi.org/10.15252/embj.201590992en
dc.identifier.issn0261-4189
dc.identifier.otherPURE: 204851414
dc.identifier.otherPURE UUID: 291756e6-3f1d-480f-a4e9-e07259fbe66d
dc.identifier.otherScopus: 84940719535
dc.identifier.otherWOS: 000360760800008
dc.identifier.otherORCID: /0000-0002-5191-0093/work/64361188
dc.identifier.urihttp://hdl.handle.net/10023/7029
dc.descriptionFunding provided by: Wellcome Trust Technology Platform 097945/B/11/Z, MRC Next Generation Optical Microscopy MR/K015869/1, Medical Research Council, Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer‐Ingelheim, GlaxoSmithKline, Merck KGaA, Janssen Pharmaceutica and Pfizer).en
dc.description.abstractLysosomes are essential organelles that function to degrade and recycle unwanted, damaged and toxic biological components. Lysosomes also act as signalling platforms in activating the nutrient-sensing kinase mTOR. mTOR regulates cellular growth, but it also helps to maintain lysosome identity by initiating lysosomal tubulation through a process termed autophagosome-lysosome reformation (ALR). Here we identify a lysosomal pool of phosphatidylinositol 3-phosphate that, when depleted by specific inhibition of the class III phosphoinositide 3-kinase VPS34, results in prolonged lysosomal tubulation. This tubulation requires mTOR activity, and we identified two direct mTOR phosphorylation sites on UVRAG (S550 and S571) that activate VPS34. Loss of these phosphorylation sites reduced VPS34 lipid kinase activity and resulted in an increase in number and length of lysosomal tubules. In cells in which phosphorylation at these UVRAG sites is disrupted, the result of impaired lysosomal tubulation alongside ALR activation is massive cell death. Our data imply that ALR is critical for cell survival under nutrient stress and that VPS34 is an essential regulatory element in this process.
dc.format.extent19
dc.language.isoeng
dc.relation.ispartofEMBO Journalen
dc.rightsCopyright 2015 The Authors. Published under the terms of the CC BY 4.0 license.en
dc.subjectLysosomeen
dc.subjectMTORen
dc.subjectTubuleen
dc.subjectUVRAGen
dc.subjectVPS34en
dc.subjectR Medicine (General)en
dc.subjectQR Microbiologyen
dc.subjectNDASen
dc.subjectBDCen
dc.subject.lccR1en
dc.subject.lccQRen
dc.titlemTOR activates the VPS34-UVRAG complex to regulate autolysosomal tubulation and cell survivalen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews.Biomedical Sciences Research Complexen
dc.contributor.institutionUniversity of St Andrews.School of Medicineen
dc.identifier.doihttps://doi.org/10.15252/embj.201590992
dc.description.statusPeer revieweden


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