New Key Publication: G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling

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.

By: 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

Read more about this Section Systems Medicine of Metabolism and Signalling CELL paper: https://www.cell.com/cell/fulltext/S0092-8674(20)31694-9