Transbilayer phospholipid movement facilitates the translocation of annexin across membranes

Annexins are cytosolic phospholipid-binding proteins that can be found on the outer leaflet of the plasma membrane. The extracellular functions of annexin include modulating fibrinolysis activity and cell migration. Despite having well-described extracellular functions, the mechanism of annexin transport from the cytoplasmic inner leaflet to the extracellular outer leaflet of the plasma membrane remains unclear. Here, we show that the transbilayer movement of phospholipids facilitates the transport of annexins A2 and A5 across membranes in cells and in liposomes. We identified TMEM16F (also known as anoctamin-6, ANO6) as a lipid scramblase required for transport of these annexins to the outer leaflet of the plasma membrane. This work reveals a mechanism for annexin translocation across membranes which depends on plasma membrane phospholipid remodelling.