BPS2026 – How forces reshape membranes: The PIEZO1-TMEM16F cascade in health and disease

PIEZO1 is a key mechanosensor at the cell surface, converting physical forces into ionic currents and downstream signaling events. Although its physiological and pathological roles are increasingly recognized, the signaling pathways downstream of PIEZO1 remain incompletely defined. Here, we describe a mechanotransduction cascade linking PIEZO1 to the calcium-activated lipid scramblase TMEM16F, which regulates membrane lipid asymmetry with broad implications for development and disease. We discovered that PIEZO1 is expressed in placental trophoblasts, where it is essential for trophoblast fusion, placental development, and fetal survival, in addition to its established role in angiogenesis. Using biophysical approaches, we established that PIEZO1-mediated calcium influx activates TMEM16F, leading to the externalization of phosphatidylserine (PS), a critical “fuse-me” signal for trophoblast fusion. We further showed that this PIEZO1-TMEM16F cascade functions in red blood cells (RBCs), where it transduces mechanical stress into membrane remodeling events including PS exposure and microparticle release. Because PS also serves as an “eat-me” signal, a procoagulant surface, and a cue for cell-cell interactions, this mechanosensitive membrane remodeling promotes RBC clearance, coagulation, and adhesion to the endothelium. Importantly, the cascade is exaggerated in hereditary xerocytosis (HX) and sickle cell disease (SCD) due to hyperactive PIEZO1, providing a molecular explanation for the long-standing observation of elevated PS exposure in sickle RBCs, a hallmark pathogenic feature of SCD. Finally, we identified benzbromarone, an antigout medicine, as a potent PIEZO1 inhibitor that disrupts this cascade, prevents RBC membrane remodeling. Therefore, pharmacological disruption of the PIEZO1-TMEM16F cascade represents a promising therapeutic strategy to mitigate thrombotic risk and/or vaso-occlusive crises in HX and SCD.