The ER tether VAPA is required for proper cell motility and for anchoring ER-plasma membrane contact sites to focal adhesions

Cell motility processes highly depend on the membrane distribution of Phosphoinositides, giving rise to cytoskeleton reshaping and membrane trafficking events. Membrane contact sites serve as platforms for lipid exchange and calcium fluxes between two organelles. Here, we show that VAPA, an ER-resident contact site tether, plays a crucial role during cell motility. CaCo2 adenocarcinoma epithelial cells depleted for VAPA exhibit several collective and individual motility defects, disorganized actin cytoskeleton and altered protrusive activity. During migration, VAPA is required for maintaining high levels of PI(4,5)P2 at the plasma membrane (PM) but not in other compartments. In addition, VAPA plays a local function at focal adhesions (FA) where it anchors and stabilizes ER-PM contact sites, thus mediating microtubule-dependent FA disassembly. Our study reveals unprecedented functions for VAPA in cell motility processes through the regulation of Phosphoinositides homeostasis and local anchoring of ER-PM contact sites to FA.