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.

Automated summary

The study found that Ras GTPase-activating protein-binding proteins 1 and 2 are core components of stress granules and play a key role at the cytoplasmic surface of lysosomes. They anchor the tuberous sclerosis complex protein complex to lysosomes in a non-redundant manner, suppressing the activation of mTORC1. Deficiency in G3BP1 can lead to phenotypes related to mTORC1 hyperactivity, and low G3BP1 levels in tumors enhance mTORC1-driven cell motility and correlate with poor outcomes in patients. Additionally, inhibition of G3bp1 in zebrafish affects neuronal development and function.