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Rap1-GTPases control mTORC1 activity by coordinating lysosome organization with amino acid availability

Anders P Mutvei1,2,3, Michal J Nagiec4, Jens C Hamann4

  • 1Weill Cornell Medicine, Sandra and Edward Meyer Cancer Center, Belfer Research Building, 413 E. 69th St., New York, NY, 10021, USA. anders.mutvei@igp.uu.se.

Nature Communications
|March 19, 2020
PubMed

Insights

Nutrient scarcity suppresses mTORC1 signaling by limiting lysosome availability. Rap1 GTPases control lysosome positioning and abundance, impacting mTORC1 activation crucial for cellular growth and cancer.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Cancer Research

Background:

  • The mTOR complex 1 (mTORC1) kinase regulates cellular growth and is often dysregulated in cancers.
  • mTORC1 activation occurs on lysosomes in response to nutrients, mediated by Rag and Rheb GTPases, driving biosynthesis.
  • The mechanisms by which nutrient limitation suppresses mTORC1 activity are not fully understood.

Purpose of the Study:

  • To investigate how nutrient limitations suppress mTORC1 signaling.
  • To elucidate the role of Rap1 GTPases in regulating lysosome dynamics and mTORC1 activity.
  • To understand the impact of lysosomal surface availability on mTORC1 signaling output.

Main Methods:

  • Investigated the effect of amino acid limitation on lysosome positioning and abundance.
  • Studied the activation of Rap1 GTPases independent of known amino acid signaling factors.
  • Assessed the impact of Rap1 activation and depletion on mTORC1 signaling and lysosome-mTORC1 association.

Main Results:

  • Amino acid limitation leads to Rap1 GTPase activation, which confines lysosomes to the perinuclear region and reduces lysosome abundance, suppressing mTORC1 signaling.
  • Rap1 activation limits the lysosomal surface available for mTORC1 activation.
  • Rap1 depletion expands lysosome populations, increasing mTORC1 association with activators and causing hyperactivity.

Conclusions:

  • Rap1 GTPases are critical coordinators of the lysosomal system in response to nutrient availability.
  • Aberrant changes in lysosomal surface availability significantly impact mTORC1 signaling output.
  • This study provides new insights into nutrient sensing pathways and their implications in cancer.

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