Lysosomal recruitment of TSC2 is a universal response to cellular stress

Nat Commun. 2016 Feb 12;7:10662. doi: 10.1038/ncomms10662.

Abstract

mTORC1 promotes cell growth and is therefore inactivated upon unfavourable growth conditions. Signalling pathways downstream of most cellular stresses converge on TSC1/2, which serves as an integration point that inhibits mTORC1. The TSC1/2 complex was shown to translocate to lysosomes to inactivate mTORC1 in response to two stresses: amino-acid starvation and growth factor removal. Whether other stresses also regulate TSC2 localization is not known. How TSC2 localization responds to combinations of stresses and other stimuli is also unknown. We show that both amino acids and growth factors are required simultaneously to maintain TSC2 cytoplasmic; when one of the two is missing, TSC2 relocalizes to lysosomes. Furthermore, multiple different stresses that inhibit mTORC1 also drive TSC2 lysosomal accumulation. Our findings indicate that lysosomal recruitment of TSC2 is a universal response to stimuli that inactivate mTORC1, and that the presence of any single stress is sufficient to cause TSC2 lysosomal localization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / metabolism
  • Animals
  • Blotting, Western
  • COS Cells
  • Cell Line
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Cytoplasm / metabolism*
  • Fluorescent Antibody Technique
  • HEK293 Cells
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • Immunoprecipitation
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Lysosomes / metabolism*
  • MCF-7 Cells
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Microscopy, Confocal
  • Multiprotein Complexes / metabolism*
  • NIH 3T3 Cells
  • Stress, Physiological*
  • TOR Serine-Threonine Kinases / metabolism*
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Amino Acids
  • Intercellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • TSC2 protein, human
  • Tsc2 protein, mouse
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1