K63 polyubiquitination and activation of mTOR by the p62-TRAF6 complex in nutrient-activated cells

Mol Cell. 2013 Aug 8;51(3):283-96. doi: 10.1016/j.molcel.2013.06.020. Epub 2013 Aug 1.

Abstract

The ability of cells to respond to changes in nutrient availability is critical for an adequate control of metabolic homeostasis. Mammalian target of rapamycin complex 1 (mTORC1) is a central complex kinase in these processes. The signaling adaptor p62 binds raptor, and integral component of the mTORC1 pathway. p62 interacts with TNF receptor associated factor 6 (TRAF6) and is required for mTORC1 translocation to the lysosome and its subsequent activation. Here we show that TRAF6 is recruited to and activates mTORC1 through p62 in amino acid-stimulated cells. We also show that TRAF6 is necessary for the translocation of mTORC1 to the lysosomes and that the TRAF6-catalyzed K63 ubiquitination of mTOR regulates mTORC1 activation by amino acids. TRAF6, through its interaction with p62 and activation of mTORC1, modulates autophagy and is an important mediator in cancer cell proliferation. Interfering with the p62-TRAF6 interaction serves to modulate autophagy and nutrient sensing.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Autophagy / physiology
  • Biological Transport
  • Cell Line
  • Cell Proliferation
  • Enzyme Activation
  • HEK293 Cells
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Lysosomes / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes / metabolism*
  • Mutation
  • NF-kappa B / metabolism
  • RNA Interference
  • RNA, Small Interfering
  • Sequestosome-1 Protein
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism*
  • TOR Serine-Threonine Kinases / metabolism*
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • Heat-Shock Proteins
  • Multiprotein Complexes
  • NF-kappa B
  • RNA, Small Interfering
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • TNF Receptor-Associated Factor 6
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1