TMEM63B channel is the mechanosensor in alveolar epithelial type II cells

Inspiration-induced mechanical stretching serves as the primary driving force for pulmonary surfactant secretion from alveolar epithelial type II (AT2) cells. However, the mechanism by which AT2 cells sense mechanical stimuli remains elusive. Here, we demonstrate that TMEM63B functions as a critical mechanosensor on the plasma membrane of AT2 cells. We find that stretch induces significant currents in AT2 cells. Using Tmem63b^HA-fl/HA-fl mice, we show that TMEM63B is expressed on the plasma membrane of AT2 cells. Deletion of TMEM63B in AT2 cells abolishes the stretch-induced currents and suppresses the secretion of pulmonary surfactant. Activation of TMEM63B causes Ca²⁺ influx, lamellar body (LB) fusion, and pulmonary surfactant secretion. These processes are markedly impaired upon TMEM63B deletion. In contrast, ATP-induced Ca²⁺ influx and LB fusion are unaffected by TMEM63B deletion, indicating that TMEM63B plays a specialized role in sensing mechanical stretch in the lungs. Therefore, our study establishes TMEM63B as a key mechanosensor critical for AT2 cell-mediated pulmonary surfactant secretion.