The following is a summary of “Deciphering and Disrupting PIEZO1-TMEM16F Interplay in Hereditary Xerocytosis,” published in the December 2023 issue of Pediatrics by Liang et al.

The exposure of phosphatidylserine (PS) on the cell surface plays a vital role in the clearance of cells through phagocytosis and blood clotting. However, the identity and activation mechanism of the calcium-activated phospholipid scramblase (CaPLSase) responsible for this process in red blood cells (RBCs) and its role in RBC biology and disease have remained enigmatic. In extensive research, researchers have successfully identified TMEM16F as the elusive CaPLSase in RBCs, demonstrating that it is activated by calcium influx through PIEZO1, a mechanosensitive channel found in RBCs. 

The study group observed an intensified functional connection between PIEZO1 and TMEM16F in RBCs obtained from individuals with hereditary xerocytosis (HX), a disorder in RBCs caused by a gain-of-function channelopathy in PIEZO1. This heightened coupling between PIEZO1 and TMEM16F increases the tendency to expose PS. This factor may significantly contribute to the clinical manifestations of HX, including anemia, splenomegaly, and thrombosis following splenectomy.

Their study further indicates that toxin GsMTx-4 and benzbromarone, a medication typically used for gout treatment, can effectively inhibit PIEZO1. This inhibition prevents force-induced changes in RBC shape (echinocytosis), hemolysis, and PS exposure in RBCs affected by HX. These findings shed light on the activation mechanism of TMEM16F CaPLSase and its pivotal role in the pathophysiology of HX, offering valuable insights that may guide potential treatments for this condition.

Source: sciencedirect.com/science/article/abs/pii/S0006497123144934