Metabolic stress controls mTORC1 lysosomal localization and dimerization by regulating the TTT-RUVBL1/2 complex

Mol Cell. 2013 Jan 10;49(1):172-85. doi: 10.1016/j.molcel.2012.10.003. Epub 2012 Nov 8.

Abstract

The metabolism of glucose and glutamine, primary carbon sources utilized by mitochondria to generate energy and macromolecules for cell growth, is directly regulated by mTORC1. We show that glucose and glutamine, by supplying carbons to the TCA cycle to produce ATP, positively feed back to mTORC1 through an AMPK-, TSC1/2-, and Rag-independent mechanism by regulating mTORC1 assembly and its lysosomal localization. We discovered that the ATP-dependent TTT-RUVBL1/2 complex was disassembled and repressed by energy depletion, resulting in its decreased interaction with mTOR. The TTT-RUVBL complex was necessary for the interaction between mTORC1 and Rag and formation of mTORC1 obligate dimers. In cancer tissues, TTT-RUVBL complex mRNAs were elevated and positively correlated with transcripts encoding proteins of anabolic metabolism and mitochondrial function-all mTORC1-regulated processes. Thus, the TTT-RUVBL1/2 complex responds to the cell's metabolic state, directly regulating the functional assembly of mTORC1 and indirectly controlling the nutrient signal from Rags to mTORC1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Adenosine Triphosphate / metabolism
  • Adenylate Kinase / metabolism
  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Carcinoma / genetics
  • Carcinoma / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Citric Acid Cycle
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • Energy Metabolism*
  • Female
  • Glucose / deficiency
  • Glutamine / deficiency
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lysosomes / metabolism*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Knockout
  • Monomeric GTP-Binding Proteins / metabolism
  • Multiprotein Complexes
  • Protein Binding
  • Protein Multimerization
  • Protein Transport
  • Proteins / metabolism*
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism
  • Signal Transduction
  • Statistics, Nonparametric
  • Stress, Physiological*
  • TOR Serine-Threonine Kinases
  • Telomere-Binding Proteins / genetics
  • Telomere-Binding Proteins / metabolism
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • Proteins
  • TSC1 protein, human
  • Tel2 protein, mouse
  • Telomere-Binding Proteins
  • Tsc1 protein, mouse
  • Tti1 protein, mouse
  • Tti2 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Glutamine
  • Adenosine Triphosphate
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka1 protein, mouse
  • Adenylate Kinase
  • ATPases Associated with Diverse Cellular Activities
  • DNA Helicases
  • RUVBL1 protein, mouse
  • RUVBL2 protein, mouse
  • Monomeric GTP-Binding Proteins
  • Glucose