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

Juan F Linares1, Angeles Duran, Tomoko Yajima

  • 1Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.

Molecular Cell
|August 6, 2013
PubMed

Insights

Tumor necrosis factor receptor-associated factor 6 (TRAF6) activates the mTORC1 pathway via the p62 protein in response to amino acids. This TRAF6-p62 interaction is crucial for cellular nutrient sensing and autophagy, impacting cancer cell proliferation.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of nutrient sensing
  • Metabolic homeostasis regulation

Background:

  • Cellular nutrient sensing is vital for metabolic homeostasis.
  • Mammalian target of rapamycin complex 1 (mTORC1) is a key kinase regulating these processes.
  • The p62 adaptor protein links nutrient availability to mTORC1 signaling.

Purpose of the Study:

  • To elucidate the role of TNF receptor associated factor 6 (TRAF6) in amino acid-mediated mTORC1 activation.
  • To investigate the mechanism by which TRAF6 influences mTORC1 localization and activity.
  • To determine the impact of the p62-TRAF6 interaction on cellular processes like autophagy and proliferation.

Main Methods:

  • Investigated protein-protein interactions between TRAF6, p62, and mTORC1 components.
  • Utilized cell-based assays to track mTORC1 translocation to lysosomes.
  • Analyzed the effect of TRAF6-catalyzed ubiquitination on mTORC1 activity.
  • Examined the modulation of autophagy and cancer cell proliferation by interfering with the p62-TRAF6 interaction.

Main Results:

  • TRAF6 is recruited to and activates mTORC1 through p62 in response to amino acid stimulation.
  • TRAF6 is essential for the lysosomal translocation and activation of mTORC1.
  • TRAF6-mediated K63 ubiquitination of mTOR regulates amino acid-induced mTORC1 activation.
  • The p62-TRAF6 interaction modulates autophagy and is implicated in cancer cell proliferation.

Conclusions:

  • TRAF6 acts as a critical upstream activator of mTORC1 signaling in response to amino acids, mediated by p62.
  • TRAF6-dependent ubiquitination and lysosomal localization are key regulatory steps for mTORC1 activation.
  • Targeting the p62-TRAF6 interaction offers a potential strategy to modulate nutrient sensing and autophagy in cancer therapy.

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