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mTOR activates the VPS 34– UVRAG complex to regulate autolysosomal tubulation and cell survival
Author(s) -
Munson Michael J,
Allen George FG,
Toth Rachel,
Campbell David G,
Lucocq John M,
Ganley Ian G
Publication year - 2015
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201590992
Subject(s) - biology , microbiology and biotechnology
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 VPS 34, 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 VPS 34. Loss of these phosphorylation sites reduced VPS 34 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 VPS 34 is an essential regulatory element in this process.