Mechanosensitive channels TMEM63A and TMEM63B mediate lung inflation–induced surfactant secretion

Pulmonary surfactant is a lipoprotein complex lining the alveolar surface to decrease the surface tension and facilitate inspiration. Surfactant deficiency is often seen in premature infants and also children and adults with respiratory distress syndrome. Mechanical stretch of alveolar type 2 epithelial (AT2) cells during lung expansion is the primary physiological factor that stimulates surfactant secretion; however, it is unclear whether there is a mechanosensor dedicated for this process. Here we show that loss of mechanosensitive channels TMEM63A and TMEM63B resulted in atelectasis and respiratory failure in mice due to deficit of surfactant secretion. TMEM63A/B were predominantly localized at the limiting membrane of lamellar body, a lysosome-related organelle that stores pulmonary surfactant and ATP in AT2 cells. Activation of TMEM63A/B channels during cell stretch facilitated release of surfactant and ATP from lamellar bodies fused with the plasma membrane. The released ATP evoked Ca2+ signaling in AT2 cells and potentiated exocytic fusion of more lamellar bodies. Our study uncovered a vital physiological function of TMEM63 mechanosensitive channels, which makes the lung ready for the first breath at birth and maintains respiration through the life.