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G3BP1 tethers the TSC complex to lysosomes and suppresses mTORC1 in the absence of stress granules

View ORCID ProfileMirja T. Prentzell, View ORCID ProfileUlrike Rehbein, View ORCID ProfileMarti Cadena Sandoval, Ann-Sofie De Meulemeester, View ORCID ProfileRalf Baumeister, View ORCID ProfileLaura Brohée, View ORCID ProfileBianca Berdel, View ORCID ProfileMathias Bockwoldt, View ORCID ProfileBernadette Carroll, Andreas von Deimling, View ORCID ProfileConstantinos Demetriades, Gianluca Figlia, View ORCID ProfileAlexander M. Heberle, View ORCID ProfileInes Heiland, Birgit Holzwarth, View ORCID ProfileLukas A. Huber, View ORCID ProfileJacek Jaworski, Katharina Kern, View ORCID ProfileAndrii Kopach, View ORCID ProfileViktor I. Korolchuk, Ineke van ’t Land-Kuper, View ORCID ProfileMatylda Macias, Mark Nellist, Stefan Pusch, Michele Reil, Anja Reintjes, Friederike Reuter, Chloë Scheldeman, Eduard Stefan, Aurelio Teleman, Omar Torres-Quesada, Saskia Trump, View ORCID ProfilePeter de Witte, View ORCID ProfileTeodor Yordanov, View ORCID ProfileChristiane A. Opitz, View ORCID ProfileKathrin Thedieck
doi: https://doi.org/10.1101/2020.04.16.044081
Mirja T. Prentzell
1Brain Cancer Metabolism Group, German Consortium of Translational Cancer Research (DKTK) & German Cancer Research Center (DKFZ), Heidelberg, Germany
2Department of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University of Groningen, University Medical Center Groningen, The Netherlands
3Department of Bioinformatics and Molecular Genetics (Faculty of Biology), University of Freiburg, Germany
4Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Germany
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  • ORCID record for Mirja T. Prentzell
Ulrike Rehbein
2Department of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University of Groningen, University Medical Center Groningen, The Netherlands
5Department for Neuroscience, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, Germany
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Marti Cadena Sandoval
2Department of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University of Groningen, University Medical Center Groningen, The Netherlands
6Institute of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Austria
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  • ORCID record for Marti Cadena Sandoval
Ann-Sofie De Meulemeester
7Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Belgium
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Ralf Baumeister
3Department of Bioinformatics and Molecular Genetics (Faculty of Biology), University of Freiburg, Germany
4Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Germany
8Signalling Research Centres BIOSS and CIBSS & ZBMZ Center for Biochemistry and Molecular Cell Research (Faculty of Medicine), University of Freiburg, Germany
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Laura Brohée
9Max Planck Institute for Biology of Ageing (MPI-AGE), Cologne, Germany
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  • ORCID record for Laura Brohée
Bianca Berdel
1Brain Cancer Metabolism Group, German Consortium of Translational Cancer Research (DKTK) & German Cancer Research Center (DKFZ), Heidelberg, Germany
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Mathias Bockwoldt
10Department of Arctic and Marine Biology, UiT The Arctic University of Norway, 9037 Tromsø, Norway
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Bernadette Carroll
11School of Biochemistry, Biomedical Sciences Building, University Walk, Bristol, UK
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Andreas von Deimling
12German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) & Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Germany
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Constantinos Demetriades
9Max Planck Institute for Biology of Ageing (MPI-AGE), Cologne, Germany
13CECAD Cluster of Excellence, University of Cologne, Germany
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Gianluca Figlia
14German Cancer Research Center (DKFZ), Heidelberg, Germany
15Heidelberg University, Heidelberg, Germany
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Alexander M. Heberle
2Department of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University of Groningen, University Medical Center Groningen, The Netherlands
6Institute of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Austria
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Ines Heiland
10Department of Arctic and Marine Biology, UiT The Arctic University of Norway, 9037 Tromsø, Norway
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Birgit Holzwarth
3Department of Bioinformatics and Molecular Genetics (Faculty of Biology), University of Freiburg, Germany
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Lukas A. Huber
16Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
17Austrian Drug Screening Institute, ADSI, Innsbruck, Austria
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Jacek Jaworski
18Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology in Warsaw, Poland
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Katharina Kern
1Brain Cancer Metabolism Group, German Consortium of Translational Cancer Research (DKTK) & German Cancer Research Center (DKFZ), Heidelberg, Germany
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Andrii Kopach
18Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology in Warsaw, Poland
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Viktor I. Korolchuk
19Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Ineke van ’t Land-Kuper
2Department of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University of Groningen, University Medical Center Groningen, The Netherlands
5Department for Neuroscience, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, Germany
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Matylda Macias
18Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology in Warsaw, Poland
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Mark Nellist
20Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
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Stefan Pusch
12German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) & Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Germany
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Michele Reil
1Brain Cancer Metabolism Group, German Consortium of Translational Cancer Research (DKTK) & German Cancer Research Center (DKFZ), Heidelberg, Germany
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Anja Reintjes
6Institute of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Austria
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Friederike Reuter
1Brain Cancer Metabolism Group, German Consortium of Translational Cancer Research (DKTK) & German Cancer Research Center (DKFZ), Heidelberg, Germany
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Chloë Scheldeman
7Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Belgium
21Neurogenetics research group, VUB, Brussels, Belgium
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Eduard Stefan
6Institute of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Austria
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Aurelio Teleman
14German Cancer Research Center (DKFZ), Heidelberg, Germany
15Heidelberg University, Heidelberg, Germany
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Omar Torres-Quesada
6Institute of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Austria
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Saskia Trump
22Molecular Epidemiology Unit, Charité-Universitätsmedizin Berlin & Berlin Institute of Health, Berlin, Germany
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Peter de Witte
7Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Belgium
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Teodor Yordanov
16Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
23Division of Cell and Developmental Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
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Christiane A. Opitz
1Brain Cancer Metabolism Group, German Consortium of Translational Cancer Research (DKTK) & German Cancer Research Center (DKFZ), Heidelberg, Germany
24Department of Neurology, University Hospital Heidelberg and National Center for Tumor Diseases, Heidelberg, Germany
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  • For correspondence: kathrin.thedieck@uibk.ac.at k.thedieck@umcg.nl kathrin.thedieck@uol.de c.opitz@dkfz.de
Kathrin Thedieck
2Department of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University of Groningen, University Medical Center Groningen, The Netherlands
5Department for Neuroscience, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, Germany
6Institute of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Austria
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  • For correspondence: kathrin.thedieck@uibk.ac.at k.thedieck@umcg.nl kathrin.thedieck@uol.de c.opitz@dkfz.de
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Summary

G3BP1 (Ras GTPase-activating protein-binding protein 1) is widely recognized as a core component of stress granules (SG), non-membranous RNA-protein-assemblies required for cellular survival under stress. We report that in the absence of SG, G3BP1 acts as lysosomal anchor of the Tuberous Sclerosis Complex (TSC) protein complex. By tethering the TSC complex to lysosomes, G3BP1 suppresses signaling through the metabolic master regulator mTORC1 (mechanistic target of rapamycin complex 1). Like the known TSC complex subunits, G3BP1 suppresses phenotypes related to mTORC1 hyperactivity in the context of tumors and neuronal dysfunction. Thus, G3BP1 is not only a core component of SG but also a key element of lysosomal TSC-mTORC1 signaling.

Highlights The bona fide stress granule component G3BP1

  • is a key element of the TSC-mTORC1 signaling axis.

  • tethers the TSC complex to lysosomes.

  • prevents mTORC1 hyperactivation by metabolic stimuli.

  • suppresses mTORC1-driven cancer cell motility and epileptiform activity.

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Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Label correction in Figure 3D; ORCID iD added for author T. Yordanov.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 22, 2020.
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G3BP1 tethers the TSC complex to lysosomes and suppresses mTORC1 in the absence of stress granules
Mirja T. Prentzell, Ulrike Rehbein, Marti Cadena Sandoval, Ann-Sofie De Meulemeester, Ralf Baumeister, Laura Brohée, Bianca Berdel, Mathias Bockwoldt, Bernadette Carroll, Andreas von Deimling, Constantinos Demetriades, Gianluca Figlia, Alexander M. Heberle, Ines Heiland, Birgit Holzwarth, Lukas A. Huber, Jacek Jaworski, Katharina Kern, Andrii Kopach, Viktor I. Korolchuk, Ineke van ’t Land-Kuper, Matylda Macias, Mark Nellist, Stefan Pusch, Michele Reil, Anja Reintjes, Friederike Reuter, Chloë Scheldeman, Eduard Stefan, Aurelio Teleman, Omar Torres-Quesada, Saskia Trump, Peter de Witte, Teodor Yordanov, Christiane A. Opitz, Kathrin Thedieck
bioRxiv 2020.04.16.044081; doi: https://doi.org/10.1101/2020.04.16.044081
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G3BP1 tethers the TSC complex to lysosomes and suppresses mTORC1 in the absence of stress granules
Mirja T. Prentzell, Ulrike Rehbein, Marti Cadena Sandoval, Ann-Sofie De Meulemeester, Ralf Baumeister, Laura Brohée, Bianca Berdel, Mathias Bockwoldt, Bernadette Carroll, Andreas von Deimling, Constantinos Demetriades, Gianluca Figlia, Alexander M. Heberle, Ines Heiland, Birgit Holzwarth, Lukas A. Huber, Jacek Jaworski, Katharina Kern, Andrii Kopach, Viktor I. Korolchuk, Ineke van ’t Land-Kuper, Matylda Macias, Mark Nellist, Stefan Pusch, Michele Reil, Anja Reintjes, Friederike Reuter, Chloë Scheldeman, Eduard Stefan, Aurelio Teleman, Omar Torres-Quesada, Saskia Trump, Peter de Witte, Teodor Yordanov, Christiane A. Opitz, Kathrin Thedieck
bioRxiv 2020.04.16.044081; doi: https://doi.org/10.1101/2020.04.16.044081

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