Automechanical gating of Piezo1 triggers the fusogenic steps in macropinocytosis

Abstract The mechanical cues that impact cell behaviour predominantly arise from the extracellular tissue microenvironment. Here, we describe a cell autonomous mechanotransduction pathway at the membrane ruffles of highly endocytic cells including macropinocytic tumors and macrophages. As ruffles extended from the cell body, the tensed membrane gated Piezo1 which led to the activation of a calcium-sensitive scramblase, TMEM16F. The local scrambling of phosphatidylserine (PS) was then captured by PS receptors, ultimately promoting membrane fusion and the entrapment of bulk fluid. Targeting PIEZO1, TMEM16F, or the PS receptor CD300A prevented macropinocytosis and arrested the growth of tumor cells that are dependent on the uptake of protein as a source of amino acids. This conserved module thus couples the mechanics of membrane ruffling to the fusion machinery required for a specialized type of ongoing endocytosis and is targetable in cancer.