mTORC1 restricts TFE3 activity by auto-regulating its presence on lysosomes
To stimulate cell growth, the protein kinase complex mTORC1 requires intracellular amino acids for activation. Amino-acid sufficiency is relayed to mTORC1 by Rag GTPases on lysosomes, where growth factor signaling enhances mTORC1 activity via the GTPase Rheb. In the absence of amino acids, GATOR1 inactivates the Rags, resulting in lysosomal detachment and inactivation of mTORC1. We demonstrate that in human cells, the release of mTORC1 from lysosomes depends on its kinase activity. In accordance with a negative feedback mechanism, activated mTOR mutants display low lysosome occupancy, causing hypo-phosphorylation and nuclear localization of the lysosomal substrate TFE3. Surprisingly, mTORC1 activated by Rheb does not increase the cytoplasmic/lysosomal ratio of mTORC1, indicating the existence of mTORC1 pools with distinct substrate specificity. Dysregulation of either pool results in aberrant TFE3 activity and may explain nuclear accumulation of TFE3 in epileptogenic malformations in focal cortical dysplasia type II (FCD II) and tuberous sclerosis (TSC).
Authors
- Holger Rehmann
- Eleonora Aronica (ORCID: https://orcid.org/0000-0002-3542-3770)
- Jasper J. Anink (ORCID: https://orcid.org/0000-0003-1292-4529)
- Susan Zwakenberg (ORCID: https://orcid.org/0000-0002-9053-2419)
- Fried Zwartkruis (ORCID: https://orcid.org/0000-0001-5775-1313)
- Marjolein Bosma (ORCID: https://orcid.org/0000-0003-3841-1983)
- Jolita Čiapaitė (ORCID: https://orcid.org/0000-0001-8761-9233)
- Nalan Liv (ORCID: https://orcid.org/0000-0003-2654-9117)
- Robert M. van Es
- Denise Westland
- Nanda M. Verhoeven‐Duif (ORCID: https://orcid.org/0000-0002-2016-5182)
- Ellen Stelloo (ORCID: https://orcid.org/0000-0002-1264-3594)
- Judith Jans (ORCID: https://orcid.org/0000-0003-0960-6263)
- Paula Sobrevals Alcaraz (ORCID: https://orcid.org/0000-0003-0035-7002)
- Harmjan R. Vos (ORCID: https://orcid.org/0000-0002-4696-6068)
Institutions
- Utrecht University (NL)
- Europa-Universität Flensburg (DE)
- University Medical Center Utrecht (NL)
- Amsterdam Neuroscience (NL)
- Oncode Institute (NL)
- Amsterdam University Medical Centers (NL)
- Stichting Epilepsie Instellingen Nederland (NL)
- University of Amsterdam (NL)
- Flensburg University of Applied Sciences (DE)
Publication Details
- Journal
- Molecular Cell
- Published
- 2024-10-31
- DOI
- https://doi.org/10.1016/j.molcel.2024.10.009
- Citations
- 14
- Primary Topic
- PI3K/AKT/mTOR signaling in cancer
- Type
- article
- Field-Weighted Citation Impact
- 3.27
Funders
- European Commission
- ZonMw
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Universitair Medisch Centrum Utrecht