Acute decrease in plasma membrane tension induces macropinocytosis via PLD2 activation

Internalization of macromolecules and membrane into cells through endocytosis is critical for cellular growth, signaling, and membrane tension homeostasis. Although endocytosis is responsive to both biochemical and physical stimuli, how physical cues modulate endocytic pathways is less understood. In contrary to the accumulating discoveries on effects of increased membrane tension on endocytosis, little is known about how a drop of tension impacts membrane trafficking. Here we reveal that acute reduction of plasma membrane tension results in phosphatidic acid, F-actin and dynamin 2-enriched dorsal membrane ruffling and subsequent macropinocytosis in myoblast. The membrane flaccidity-induced local phosphatidic acid production depends on phospholipase D2 (PLD2) that is activated via lipid raft disruption. Furthermore, the membrane flaccidity-PLD2-macropinocytosis pathway is dominant in myotube, reflecting a potential mechanism of membrane tension homeostasis upon intensive muscle stretching and relaxation. Together, we identify a new mechanotransduction pathway which converts acute tension drop into PA production and subsequently initiates macropinocytosis via actin and dynamin activities.