G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling,Cell

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G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling
Cell ( IF 45.5 ) Pub Date : 2021-01-25 , DOI: 10.1016/j.cell.2020.12.024
Mirja Tamara Prentzell ₁ , Ulrike Rehbein ₂ , Marti Cadena Sandoval ₃ , Ann-Sofie De Meulemeester ₄ , Ralf Baumeister ₅ , Laura Brohée ₆ , Bianca Berdel ₇ , Mathias Bockwoldt ₈ , Bernadette Carroll ₉ , Suvagata Roy Chowdhury ₁₀ , Andreas von Deimling ₁₁ , Constantinos Demetriades ₁₂ , Gianluca Figlia ₁₃ , , Mariana Eca Guimaraes de Araujo ₁₄ , Alexander M Heberle ₃ , Ines Heiland ₈ , Birgit Holzwarth ₁₅ , Lukas A Huber ₁₆ , Jacek Jaworski ₁₇ , Magdalena Kedra ₁₇ , Katharina Kern ₇ , Andrii Kopach ₁₇ , Viktor I Korolchuk ₁₈ , Ineke van 't Land-Kuper ₁₉ , Matylda Macias ₁₇ , Mark Nellist ₂₀ , Wilhelm Palm ₁₀ , Stefan Pusch ₁₁ , Jose Miguel Ramos Pittol ₂₁ , Michèle Reil ₇ , Anja Reintjes ₂₁ , Friederike Reuter ₇ , Julian R Sampson ₂₂ , Chloë Scheldeman ₂₃ , Aleksandra Siekierska ₄ , Eduard Stefan ₂₁ , Aurelio A Teleman ₁₃ , Laura E Thomas ₂₄ , Omar Torres-Quesada ₂₁ , Saskia Trump ₂₅ , Hannah D West ₂₂ , Peter de Witte ₄ , Sandra Woltering ₇ , Teodor E Yordanov ₂₆ , Justyna Zmorzynska ₁₇ , Christiane A Opitz ₂₇ , Kathrin Thedieck ₂

Affiliation

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.
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.
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.
Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven BE-3000, Belgium.
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.
Cell Growth Control in Health and Age-Related Disease Group, Max Planck Institute for Biology of Ageing (MPI-AGE), Cologne 50931, Germany.
Brain Cancer Metabolism Group, German Consortium of Translational Cancer Research (DKTK) & German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
Department of Arctic and Marine Biology, UiT The Arctic University of Norway, Tromsø 9037, Norway.
School of Biochemistry, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, UK.
Cell Signaling and Metabolism Group, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
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.
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.
Signal Transduction in Cancer and Metabolism, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Heidelberg University, Heidelberg 69120, Germany.
Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria.
Department of Bioinformatics and Molecular Genetics (Faculty of Biology), University of Freiburg, Freiburg 79104, Germany.
Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria; Austrian Drug Screening Institute (ADSI), Innsbruck 6020, Austria.
Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology in Warsaw, Warsaw 02-109, Poland.
Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
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.
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam 3015 GD, The Netherlands.
Institute of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck 6020, Austria.
Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University Medical School, Cardiff CF14 4AY, UK.
Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven BE-3000, Belgium; Neurogenetics Research Group, VUB, Brussels 1090, Belgium.
Institute of Life Science, Swansea University, Swansea SA2 8PP, UK.
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.
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.
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.

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.

中文翻译：

G3BP 将 TSC 复合物束缚在溶酶体上并抑制 mTORC1 信号传导

Ras GTP 酶激活蛋白结合蛋白 1 和 2（分别为 G3BP1 和 G3BP2）被广泛认为是应激颗粒 (SG) 的核心成分。我们报告 G3BP 位于溶酶体的细胞质表面。它们以非冗余的方式发挥作用，将结节性硬化症复合物 (TSC) 蛋白复合物锚定在溶酶体上，并抑制氨基酸和胰岛素对雷帕霉素复合物 1 (mTORC1) 代谢主调节机制靶点的激活。与 TSC 复合体一样，G3BP1 缺陷会引发与 mTORC1 过度活跃相关的表型。在肿瘤中，低 G3BP1 水平会增强 mTORC1 驱动的乳腺癌细胞运动性，并与患者的不良后果相关。此外，斑马鱼中的 G3bp1 抑制会扰乱神经元发育和功能，导致白质异位和神经元过度活跃。因此，G3BP不仅是SG的核心成分，而且还是溶酶体TSC-mTORC1信号传导的关键元件。

更新日期：2021-02-04

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