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Stability of the endosomal scaffold protein LAMTOR3 depends on heterodimer assembly and proteasomal degradation

Mariana E G de Araújo1, Taras Stasyk, Nicole Taub

  • 1Biocenter, Division of Cell Biology, Innsbruck Medical University, A-6020 Innsbruck, Austria.

The Journal of Biological Chemistry
|May 9, 2013
PubMed

Insights

Loss of LAMTOR2 destabilizes LAMTOR3, leading to its proteasomal degradation. This highlights how cellular quality control monitors Ragulator complex assembly to prevent aberrant MAPK and mTOR signaling.

Area of Science:

  • Cell Biology
  • Molecular Signaling
  • Protein Degradation

Background:

  • LAMTOR3 (MP1) and LAMTOR2 (p14) form a heterodimer within the Ragulator complex.
  • The Ragulator complex is crucial for MAPK and mTOR signaling pathways originating from late endosomes/lysosomes.

Purpose of the Study:

  • To investigate the impact of LAMTOR2 loss on LAMTOR3 stability and degradation pathways.
  • To explore the role of cellular quality control in regulating Ragulator complex assembly and function.

Main Methods:

  • Analysis of LAMTOR3 stability in cells lacking LAMTOR2.
  • Proteasomal and lysosomal inhibitor treatments.
  • Mutational analysis of LAMTOR3 lysine residues.
  • Assessment of other Ragulator subunits' stability upon LAMTOR2 depletion.

Main Results:

  • Loss of LAMTOR2 leads to an unstable cytosolic pool of monomeric LAMTOR3.
  • Monomeric LAMTOR3 undergoes rapid proteasome-dependent, lysosome-independent degradation.
  • LAMTOR3 turnover is regulated by ubiquitination at specific lysine residues.
  • Depletion of LAMTOR2 also causes degradation of LAMTOR1, LAMTOR4, and LAMTOR5.

Conclusions:

  • Ragulator complex assembly is tightly monitored by cellular quality control mechanisms.
  • The degradation of unassembled subunits prevents aberrant signaling from defective Ragulator complexes.
  • This quality control system is essential for maintaining the integrity of MAPK and mTOR signaling pathways.
Keywords:
LAMTOR1 (p18)LAMTOR2 (p14)LAMTOR3 (MP1)LAMTOR4 (c7orf59)MAP Kinases (MAPKs)Protein DegradationScaffold ProteinsSignal Transductionand LAMTOR5 (HBXIP)mTOR

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