mTOR activates the VPS34-UVRAG complex to regulate autolysosomal tubulation and cell survival

Michael J. Munson, George F. G. Allen, Rachel Toth, David G. Campbell, John M. Lucocq, Ian G. Ganley (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2272-2290
Number of pages19
JournalEMBO Journal
Volume34
Issue number17
Early online date2 Jul 2015
DOIs
Publication statusPublished - 2 Sep 2015

Keywords

  • Lysosome
  • mTOR
  • Tubule
  • UVRAG
  • VPS34

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