Mechanical cue regulates cargo sorting and export at the Golgi

The secretory pathway is a sophisticated endomembrane machinery designed to transport and deliver proteins and lipids to intracellular organelles and the extracellular space. While the molecular components of the secretory pathway are well understood, less is known about their regulation, especially by mechanical cues. Here, we report that substrate stiffness stimulates conventional secretion. We have unravelled a molecular pathway that links a mechanical cue through Src and FAK kinases to promote the trafficking of secretory proteins out of the Golgi apparatus and prevent their post-Golgi lysosomal degradation. Phosphoproteomic analysis revealed the Golgi-specific Brefeldin A resistance factor 1 (GBF1) as a downstream key mechano-responsive regulator of post-Golgi sorting. Together, our data reveal a molecular regulatory loop in which the matrix stiffness positively regulates cellular secretion via the Src-FAK-GBF1 axis, which can have relevant medical implication in conditions like cancer and fibrosis and their treatment.