mTOR activates the VPS34-UVRAG complex to regulate autolysosomal tubulation and cell survival
| Autor: | John M. Lucocq, Ian G. Ganley, Michael J. Munson, Rachel Toth, George F. G. Allen, David G. Campbell |
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| Přispěvatelé: | University of St Andrews. Biomedical Sciences Research Complex, University of St Andrews. School of Medicine |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Programmed cell death
Lipid kinase activity NDAS UVRAG Biology R Medicine (General) environment and public health General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences 0302 clinical medicine Lysosome medicine Animals Humans News & Views Phosphorylation Molecular Biology health care economics and organizations PI3K/AKT/mTOR pathway VPS34 030304 developmental biology 0303 health sciences General Immunology and Microbiology Cell growth Kinase TOR Serine-Threonine Kinases Tumor Suppressor Proteins General Neuroscience MTOR QR Microbiology Class III Phosphatidylinositol 3-Kinases R1 Cell biology QR HEK293 Cells medicine.anatomical_structure Multiprotein Complexes Tubule Lysosomes BDC 030217 neurology & neurosurgery HeLa Cells |
| Popis: | Funding 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). Lysosomes 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. Publisher PDF |
| Databáze: | OpenAIRE |
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