G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling

Mirja Tamara Prentzell; Ulrike Rehbein; Marti Cadena Sandoval; Ann-Sofie De Meulemeester; Ralf Baumeister; Laura Brohée; Bianca Berdel; Mathias Bockwoldt; Bernadette Carroll; Suvagata Roy Chowdhury; Andreas von Deimling; Constantinos Demetriades; Gianluca Figlia; Genomics England Research Consortium; Mariana Eca Guimaraes de Araujo; Alexander M Heberle; Ines Heiland; Birgit Holzwarth; Lukas A Huber; Jacek Jaworski; Magdalena Kedra; Katharina Kern; Andrii Kopach; Viktor I Korolchuk; Ineke van 't Land-Kuper; Matylda Macias; Mark Nellist; Wilhelm Palm; Stefan Pusch; Jose Miguel Ramos Pittol; Michèle Reil; Anja Reintjes; Friederike Reuter; Julian R Sampson; Chloë Scheldeman; Aleksandra Siekierska; Eduard Stefan; Aurelio A Teleman; Laura E Thomas; Omar Torres-Quesada; Saskia Trump; Hannah D West; Peter de Witte; Sandra Woltering; Teodor E Yordanov; Justyna Zmorzynska; Christiane A Opitz; Kathrin Thedieck

doi:10.1016/j.cell.2020.12.024

G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling

Cell. 2021 Feb 4;184(3):655-674.e27. doi: 10.1016/j.cell.2020.12.024. Epub 2021 Jan 25.

Authors

Mirja Tamara Prentzell¹, Ulrike Rehbein², Marti Cadena Sandoval³, Ann-Sofie De Meulemeester⁴, Ralf Baumeister⁵, Laura Brohée⁶, Bianca Berdel⁷, Mathias Bockwoldt⁸, Bernadette Carroll⁹, Suvagata Roy Chowdhury¹⁰, Andreas von Deimling¹¹, Constantinos Demetriades¹², Gianluca Figlia¹³; Genomics England Research Consortium; Mariana Eca Guimaraes de Araujo¹⁴, Alexander M Heberle³, Ines Heiland⁸, Birgit Holzwarth¹⁵, Lukas A Huber¹⁶, Jacek Jaworski¹⁷, Magdalena Kedra¹⁷, Katharina Kern⁷, Andrii Kopach¹⁷, Viktor I Korolchuk¹⁸, Ineke van 't Land-Kuper¹⁹, Matylda Macias¹⁷, Mark Nellist²⁰, Wilhelm Palm¹⁰, Stefan Pusch¹¹, Jose Miguel Ramos Pittol²¹, Michèle Reil⁷, Anja Reintjes²¹, Friederike Reuter⁷, Julian R Sampson²², Chloë Scheldeman²³, Aleksandra Siekierska⁴, Eduard Stefan²¹, Aurelio A Teleman¹³, Laura E Thomas²⁴, Omar Torres-Quesada²¹, Saskia Trump²⁵, Hannah D West²², Peter de Witte⁴, Sandra Woltering⁷, Teodor E Yordanov²⁶, Justyna Zmorzynska¹⁷, Christiane A Opitz²⁷, Kathrin Thedieck²⁸

Affiliations

¹ Brain Cancer Metabolism Group, German Consortium of Translational Cancer Research (DKTK) & German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Department of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, The Netherlands; Department of Bioinformatics and Molecular Genetics (Faculty of Biology), University of Freiburg, Freiburg 79104, Germany; Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg 79104, Germany.
² Department of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, The Netherlands; Department for Neuroscience, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, Oldenburg 26129, Germany; Institute of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck 6020, Austria.
³ Department of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, The Netherlands; Institute of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck 6020, Austria.
⁴ Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven BE-3000, Belgium.
⁵ Department of Bioinformatics and Molecular Genetics (Faculty of Biology), University of Freiburg, Freiburg 79104, Germany; Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg 79104, Germany; Signalling Research Centres BIOSS and CIBSS & ZBMZ Center for Biochemistry and Molecular Cell Research (Faculty of Medicine), University of Freiburg, Freiburg 79104, Germany.
⁶ Cell Growth Control in Health and Age-Related Disease Group, Max Planck Institute for Biology of Ageing (MPI-AGE), Cologne 50931, Germany.
⁷ Brain Cancer Metabolism Group, German Consortium of Translational Cancer Research (DKTK) & German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
⁸ Department of Arctic and Marine Biology, UiT The Arctic University of Norway, Tromsø 9037, Norway.
⁹ School of Biochemistry, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, UK.
¹⁰ Cell Signaling and Metabolism Group, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
¹¹ German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Department of Neuropathology, Institute of Pathology, Heidelberg University, Heidelberg 69120, Germany.
¹² Cell Growth Control in Health and Age-Related Disease Group, Max Planck Institute for Biology of Ageing (MPI-AGE), Cologne 50931, Germany; CECAD Cluster of Excellence, University of Cologne, Cologne 50931, Germany.
¹³ Signal Transduction in Cancer and Metabolism, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Heidelberg University, Heidelberg 69120, Germany.
¹⁴ Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria.
¹⁵ Department of Bioinformatics and Molecular Genetics (Faculty of Biology), University of Freiburg, Freiburg 79104, Germany.
¹⁶ Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria; Austrian Drug Screening Institute (ADSI), Innsbruck 6020, Austria.
¹⁷ Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology in Warsaw, Warsaw 02-109, Poland.
¹⁸ Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
¹⁹ Department of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, The Netherlands; Department for Neuroscience, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, Oldenburg 26129, Germany.
²⁰ Department of Clinical Genetics, Erasmus Medical Center, Rotterdam 3015 GD, The Netherlands.
²¹ Institute of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck 6020, Austria.
²² Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University Medical School, Cardiff CF14 4AY, UK.
²³ Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven BE-3000, Belgium; Neurogenetics Research Group, VUB, Brussels 1090, Belgium.
²⁴ Institute of Life Science, Swansea University, Swansea SA2 8PP, UK.
²⁵ Molecular Epidemiology Unit, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin 13353, Germany.
²⁶ Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria; Division of Cell and Developmental Biology, Institute for Molecular Bioscience, University of Queensland, St Lucia QLD 4072, Australia.
²⁷ Brain Cancer Metabolism Group, German Consortium of Translational Cancer Research (DKTK) & German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Department of Neurology, University Hospital Heidelberg and National Center for Tumor Diseases, Heidelberg 69120, Germany. Electronic address: c.opitz@dkfz.de.
²⁸ Department of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, The Netherlands; Department for Neuroscience, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, Oldenburg 26129, Germany; Institute of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck 6020, Austria. Electronic address: kathrin.thedieck@uibk.ac.at.

Abstract

Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that G3BPs reside at the cytoplasmic surface of lysosomes. They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress activation of the metabolic master regulator mechanistic target of rapamycin complex 1 (mTORC1) by amino acids and insulin. Like the TSC complex, G3BP1 deficiency elicits phenotypes related to mTORC1 hyperactivity. In the context of tumors, low G3BP1 levels enhance mTORC1-driven breast cancer cell motility and correlate with adverse outcomes in patients. Furthermore, G3bp1 inhibition in zebrafish disturbs neuronal development and function, leading to white matter heterotopia and neuronal hyperactivity. Thus, G3BPs are not only core components of SGs but also a key element of lysosomal TSC-mTORC1 signaling.

Keywords: G3BP1; G3BP2; TSC complex; cancer; lysosome; mTORC1; metabolism; neuronal function; stress granule.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism*
Amino Acid Sequence
Animals
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Line, Tumor
Cell Movement / drug effects
Cytoplasmic Granules / drug effects
Cytoplasmic Granules / metabolism
DNA Helicases / chemistry
DNA Helicases / metabolism*
Evolution, Molecular
Female
Humans
Insulin / pharmacology
Lysosomal Membrane Proteins / metabolism
Lysosomes / drug effects
Lysosomes / metabolism*
Mechanistic Target of Rapamycin Complex 1 / metabolism*
Neurons / drug effects
Neurons / metabolism
Phenotype
Poly-ADP-Ribose Binding Proteins / chemistry
Poly-ADP-Ribose Binding Proteins / metabolism*
RNA Helicases / chemistry
RNA Helicases / metabolism*
RNA Recognition Motif Proteins / chemistry
RNA Recognition Motif Proteins / metabolism*
RNA-Binding Proteins / metabolism*
Rats
Rats, Wistar
Signal Transduction* / drug effects
Tuberous Sclerosis / metabolism*
Zebrafish / metabolism

Substances

Adaptor Proteins, Signal Transducing
G3BP2 protein, human
Insulin
Lysosomal Membrane Proteins
Poly-ADP-Ribose Binding Proteins
RNA Recognition Motif Proteins
RNA-Binding Proteins
Mechanistic Target of Rapamycin Complex 1
DNA Helicases
G3BP1 protein, human
RNA Helicases

Abstract

Publication types

MeSH terms

Substances

Grants and funding