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Methods to Classify Cytoplasmic Foci as Mammalian Stress Granules
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Lysosomal recruitment of TSC2 is a universal response to cellular stress

Constantinos Demetriades1, Monika Plescher1, Aurelio A Teleman1

  • 1Division of Signal Transduction in Cancer and Metabolism, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

Nature Communications
|February 13, 2016
PubMed

Insights

The mechanistic target of rapamycin complex 1 (mTORC1) pathway is inhibited when cells face stress. Stress causes the TSC1/2 complex to move to lysosomes, inactivating mTORC1.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates cell growth and is inactivated under unfavorable conditions.
  • Signaling pathways from cellular stresses converge on the TSC1/2 complex, which inhibits mTORC1.
  • TSC1/2 complex translocation to lysosomes inactivates mTORC1 in response to amino acid starvation and growth factor withdrawal.

Purpose of the Study:

  • To investigate whether other stresses regulate TSC2 localization.
  • To understand how TSC2 localization responds to combined stresses and stimuli.

Main Methods:

  • Cellular localization studies of the TSC2 protein.
  • Analysis of mTORC1 activity under various stress conditions.
  • Investigating the role of amino acids and growth factors in TSC2 localization.

Main Results:

  • Both amino acids and growth factors are simultaneously required to maintain TSC2 in the cytoplasm.
  • Absence of either amino acids or growth factors causes TSC2 to relocalize to lysosomes.
  • Multiple stresses that inhibit mTORC1 also induce TSC2 lysosomal accumulation.

Conclusions:

  • Lysosomal recruitment of TSC2 is a universal response to stimuli that inactivate mTORC1.
  • The presence of any single stress is sufficient to trigger TSC2 lysosomal localization.
  • TSC2 lysosomal localization serves as a key mechanism for mTORC1 inhibition under diverse stress conditions.

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