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

SummaryG3BP1 (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.HighlightsThebona fidestress granule component G3BP1is 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.Graphical Abstract