G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling

Genomics England Research Consortium

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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.

Original languageEnglish
Pages (from-to)655-674.e27
Number of pages48
JournalCell
Volume184
Issue number3
Early online date25 Jan 2021
DOIs
Publication statusPublished - 4 Feb 2021

Bibliographical note

Funding Information:
We thank the DKFZ Light Microscopy Facility; M.N. Hall for TSC1 and TSC2 antibodies ( Molle, 2006 ); D. Esposito for Addgene plasmids 70422 and 70640; Q. Luo for the bFos-myc-LC151 and bJun-HA-LN-151 plasmids; M. Orger for Tg(HuC:GCaMP5G); M. Ekker for Tg(dlx5a/dlx6a-EGFP); S. Higashijima for Tg(vglut2a:loxP-RFP-loxP-GFP); J. Maes for zebrafish microinjections; the Cell and Tissue Imaging Cluster (CIC) for microscopy supported by Hercules AKUL/11/37 and FWO G.0929.15 (to P. Vanden Berghe); and J. Utikal and his lab, K. Breuker, S.A. Fernandes, L.F. Somarribas Patterson, M. Rodriguez Peiris, and A. Sadik for support and helpful discussions. We acknowledge support from research awards from the German Tuberous Sclerosis Foundation 2019 (to M.T.P.) and 2017 (to K.T.); the German Research Foundation ( Excellence Initiative GSC-4, Spemann Graduate School to M.T.P.; TH 1358/3- 1 to K.T.; SFB 430 1389–UNITE Glioblastoma to A.v.D., S.P., and C.A.O.; and Germany’s Excellence Strategy EXC 294 and EXC-2189-Projektnummer 390939984 , CRC850 , and CRC1381 to R.B.); the Graduate School of Medical Sciences of the University of Groningen (to M.C.S.); the German TS Foundation (to K.T.); Stichting TSC Fonds (to K.T. and M.N.); TS Alliance and TS Association UK (to M.N.); BMBF e:Med initiatives MAPTor-NET ( 031A426B to K.T.), GlioPATH ( 01ZX1402 to C.A.O., K.T., and S.T.); a Rosalind Franklin Fellowship of the University of Groningen (to K.T.); the PoLiMeR Innovative Training Network (Marie Skłodowska-Curie grant agreement 812616 to K.T.) and the MESI-STRAT project (grant agreement 754688 to C.A.O., I.H., and K.T.), which received funding from the European Union Horizon 2020 Research and Innovation Program ; the European Research Council (ERC) under the European Union Horizon 2020 Research and Innovation Program (grant agreement 757729 ) and the Max Planck Society (to C.D.); the Austrian Science Fund ( FWF DK W11 and P32608 to T.Y. and L.A.H.); the Molecular Cell Biology and Oncology PhD Program at the Medical University of Innsbruck (MCBO; to T.Y. and L.A.H.); the Fund for O6260 Research Foundation–Flanders (FWO; 11F2919N to A.-S.d.M.), the British Skin Foundation and Vice-Chancellor’s Fellowship , University of Bristol (to B.C.); a long-term EMBO postdoctoral fellowship ( ALT-755-2018 to G.F.); a TEAM grant from the Foundation for Polish Science ( POIR.04.04.00-00-5CBE/17-00 to J.J. and A.K.); a Polish National Science Centre Etiuda grant ( 2020/36/T/NZ3/00132 to M.K.); the University of Leuven (grant C32/18/067 to A.S.); a Fellowship for Extraordinary Young Scientists from the Polish Ministry of Science and Higher Education (to J.Z.); and a Sêr Cymru II Precision Medicine Fellowship (to H.W.). This research was made possible by access to the data and findings generated by the 100,000 Genomes Project, managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care) and funded by the National Institute for Health Research and NHS England . The Wellcome Trust , Cancer Research UK , and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. The Genomics England Research Consortium members and affiliations can be found online with this article in the Document S2 .

Funding Information:
We thank the DKFZ Light Microscopy Facility; M.N. Hall for TSC1 and TSC2 antibodies (Molle, 2006); D. Esposito for Addgene plasmids 70422 and 70640; Q. Luo for the bFos-myc-LC151 and bJun-HA-LN-151 plasmids; M. Orger for Tg(HuC:GCaMP5G); M. Ekker for Tg(dlx5a/dlx6a-EGFP); S. Higashijima for Tg(vglut2a:loxP-RFP-loxP-GFP); J. Maes for zebrafish microinjections; the Cell and Tissue Imaging Cluster (CIC) for microscopy supported by Hercules AKUL/11/37 and FWO G.0929.15 (to P. Vanden Berghe); and J. Utikal and his lab, K. Breuker, S.A. Fernandes, L.F. Somarribas Patterson, M. Rodriguez Peiris, and A. Sadik for support and helpful discussions. We acknowledge support from research awards from the German Tuberous Sclerosis Foundation 2019 (to M.T.P.) and 2017 (to K.T.); the German Research Foundation (Excellence Initiative GSC-4, Spemann Graduate School to M.T.P.; TH 1358/3-1 to K.T.; SFB 430 1389?UNITE Glioblastoma to A.v.D. S.P. and C.A.O.; and Germany's Excellence Strategy EXC 294 and EXC-2189-Projektnummer 390939984, CRC850, and CRC1381 to R.B.); the Graduate School of Medical Sciences of the University of Groningen (to M.C.S.); the German TS Foundation (to K.T.); Stichting TSC Fonds (to K.T. and M.N.); TS Alliance and TS Association UK (to M.N.); BMBF e:Med initiatives MAPTor-NET (031A426B to K.T.), GlioPATH (01ZX1402 to C.A.O. K.T. and S.T.); a Rosalind Franklin Fellowship of the University of Groningen (to K.T.); the PoLiMeR Innovative Training Network (Marie Sk?odowska-Curie grant agreement 812616 to K.T.) and the MESI-STRAT project (grant agreement 754688 to C.A.O. I.H. and K.T.), which received funding from the European Union Horizon 2020 Research and Innovation Program; the European Research Council (ERC) under the European Union Horizon 2020 Research and Innovation Program (grant agreement 757729) and the Max Planck Society (to C.D.); the Austrian Science Fund (FWF DK W11 and P32608 to T.Y. and L.A.H.); the Molecular Cell Biology and Oncology PhD Program at the Medical University of Innsbruck (MCBO; to T.Y. and L.A.H.); the Fund for O6260 Research Foundation?Flanders (FWO; 11F2919N to A.-S.d.M.), the British Skin Foundation and Vice-Chancellor's Fellowship, University of Bristol (to B.C.); a long-term EMBO postdoctoral fellowship (ALT-755-2018 to G.F.); a TEAM grant from the Foundation for Polish Science (POIR.04.04.00-00-5CBE/17-00 to J.J. and A.K.); a Polish National Science Centre Etiuda grant (2020/36/T/NZ3/00132 to M.K.); the University of Leuven (grant C32/18/067 to A.S.); a Fellowship for Extraordinary Young Scientists from the Polish Ministry of Science and Higher Education (to J.Z.); and a S?r Cymru II Precision Medicine Fellowship (to H.W.). This research was made possible by access to the data and findings generated by the 100,000 Genomes Project, managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care) and funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. The Genomics England Research Consortium members and affiliations can be found online with this article in the Document S2. M.T.P. U.R. and M.C.S. planned/conducted/analyzed experiments and wrote the manuscript. A.M.H. B.B. B.H. K.K. I.v.t.L.-K. M.R. A.R. F.R. and S.W. supported the experiments. A.M.H. A.K. L.B. and C.D. supported in-depth data interpretation. R.B. supported project initiation. J.M.R.P. and S.P. performed cloning. S.P. and A.v.D supported BiFC. A.-S.d.M. M.K. C.S. A.S. P.d.W. J.Z. and J.J. performed zebrafish analyses. S.R.C. and W.P. performed lyso-preps. M.B. and I.H. performed phylogenetic analyses. B.C. and V.I.K. performed IF. G.F. and A.A.T. performed TSC2-LAMP2 PLAs. M.E.G.d.A. supported cell size analyses. M.N. L.A.H. and T.Y. supported CRISPR experiments. M.M. and J.J. performed rat brain IP. O.T.-Q. and E.S. performed IP for Figure 5B. S.T. analyzed expression data. L.E.T. J.R.S. and H.D.W. analyzed GEL data. C.A.O. and K.T. planned/guided the project and wrote the manuscript. All authors participated in in-depth discussions and revised the manuscript. Apart from first/last authors, all authors are listed alphabetically. The authors declare no competing interests.

Publisher Copyright:
© 2021 The Authors

Keywords

  • TSC complex
  • mTORC1
  • G3BP1
  • G3BP2
  • lysosome
  • stress granule
  • metabolism
  • cancer
  • neuronal function

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