Proteolytic cleavage of G3BP1 by calpain 1 couples NMDAR activation to mTOR-dependent local translation

Abstract

Ribonucleoprotein (RNP) granules are dynamic, membraneless organelles that sequester translationally repressed mRNAs and RNA-binding proteins, playing a pivotal role in the regulation of localized protein synthesis. While disassembly of RNP granules is essential for reactivating translation, the mechanisms by which neuronal activity regulates this process remain poorly understood. In this study, we show that stimulation of N-methyl-D-aspartate (NMDA) receptor (NMDAR) triggers calcium influx, leading to activation of calpain 1 and subsequent proteolytic cleavage of Ras-GTPase-activating protein binding protein 1 (G3BP1), a core component of stress granules. This cleavage results in the disassembly of G3BP1 granules in the neurites and promotes mTOR-dependent local translation, thereby linking synaptic activity to spatially restricted protein synthesis. Finally, we demonstrate that the NMDAR-calpain 1-G3BP1-mTOR signaling axis contributes to axonal regeneration, establishing proteolytic remodeling of RNP granules as a key mechanism of activity-dependent neural repair, with potential implications for therapeutic intervention in brain injury.