The proteolysis of ZP proteins is essential to control cell membrane structure and integrity of developing tubes

Membrane expansion integrates multiple forces to mediate precise tube growth and network formation. Defects lead to deformations, as found in diseases such as polycystic kidney diseases, aortic aneurysms, stenosis, and tortuosity. We identified a mechanism of sensing and responding to the membrane expansion of tracheal tubes. We show in Drosophila that Zona Pellucida domain proteins Piopio and Dumpy cooperate to integrate mechanical stress at cell membranes and luminal matrix. When tension appears at the apical membrane due to tracheal tube length expansion, Piopio undergoes ectodomain shedding by the Matriptase homolog Notopleural, which releases Piopio-mediated linkages between membranes and extracellular matrix. Failure of this process leads to deformations of the apical membrane and comprises tubular network function. We also show conserved ectodomain shedding by the human matriptase during TGF-β signaling, both of which are required in the lung, providing novel approaches for in-depth analysis of pulmonary diseases caused by cell and tube shape changes.