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

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  • Anders P. Mutvei

    (Sandra and Edward Meyer Cancer Center, Belfer Research Building
    Tumor and Cell biology, Nobels väg 16, KI Solna Campus Karolinska Institutet, Box 280
    Uppsala University, Rudbeck Laboratory)

  • Michal J. Nagiec

    (Sandra and Edward Meyer Cancer Center, Belfer Research Building)

  • Jens C. Hamann

    (Sandra and Edward Meyer Cancer Center, Belfer Research Building)

  • Sang Gyun Kim

    (Sandra and Edward Meyer Cancer Center, Belfer Research Building)

  • C. Theresa Vincent

    (Uppsala University, Rudbeck Laboratory
    New York University School of Medicine)

  • John Blenis

    (Sandra and Edward Meyer Cancer Center, Belfer Research Building)

Abstract

The kinase mTOR complex 1 (mTORC1) promotes cellular growth and is frequently dysregulated in cancers. In response to nutrients, mTORC1 is activated on lysosomes by Rag and Rheb guanosine triphosphatases (GTPases) and drives biosynthetic processes. How limitations in nutrients suppress mTORC1 activity remains poorly understood. We find that when amino acids are limited, the Rap1-GTPases confine lysosomes to the perinuclear region and reduce lysosome abundance, which suppresses mTORC1 signaling. Rap1 activation, which is independent of known amino acid signaling factors, limits the lysosomal surface available for mTORC1 activation. Conversely, Rap1 depletion expands the lysosome population, which markedly increases association between mTORC1 and its lysosome-borne activators, leading to mTORC1 hyperactivity. Taken together, we establish Rap1 as a critical coordinator of the lysosomal system, and propose that aberrant changes in lysosomal surface availability can impact mTORC1 signaling output.

Suggested Citation

  • Anders P. Mutvei & Michal J. Nagiec & Jens C. Hamann & Sang Gyun Kim & C. Theresa Vincent & John Blenis, 2020. "Rap1-GTPases control mTORC1 activity by coordinating lysosome organization with amino acid availability," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15156-5
    DOI: 10.1038/s41467-020-15156-5
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    Cited by:

    1. George K. E. Umanah & Leire Abalde-Atristain & Mohammed Repon Khan & Jaba Mitra & Mohamad Aasif Dar & Melissa Chang & Kavya Tangella & Amy McNamara & Samuel Bennett & Rong Chen & Vasudha Aggarwal & Ma, 2022. "AAA + ATPase Thorase inhibits mTOR signaling through the disassembly of the mTOR complex 1," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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