mTORC1 restricts TFE3 activity by auto-regulating its presence on lysosomes.

Autor:	Zwakenberg S; Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands., Westland D; Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands., van Es RM; Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands., Rehmann H; Department of Energy and Life Science, Flensburg University of Applied Sciences, Flensburg, Germany., Anink J; Department of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands., Ciapaite J; Department of Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, 3584 EA Utrecht, the Netherlands., Bosma M; Department of Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, 3584 EA Utrecht, the Netherlands., Stelloo E; Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands., Liv N; Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands., Sobrevals Alcaraz P; Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands., Verhoeven-Duif NM; Department of Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, 3584 EA Utrecht, the Netherlands., Jans JJM; Department of Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, 3584 EA Utrecht, the Netherlands., Vos HR; Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands., Aronica E; Department of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands; Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, the Netherlands., Zwartkruis FJT; Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands. Electronic address: g.j.t.zwartkruis@umcutrecht.nl.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2024 Nov 21; Vol. 84 (22), pp. 4368-4384.e6. Date of Electronic Publication: 2024 Oct 31.
DOI:	10.1016/j.molcel.2024.10.009
Abstrakt:	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). Competing Interests: Declaration of interests E.A. has served on the scientific advisory boards of UCB and Nutricia. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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