βA3/A1-crystallin regulates apical polarity and EGFR endocytosis in retinal pigmented epithelial cells

The retinal pigmented epithelium (RPE) is a monolayer of multifunctional cells located at the back of the eye. High membrane turnover and polarization, including formation of actin-based apical microvilli, are essential for RPE function and retinal health. Herein, we demonstrate an important role for beta A3/A1-crystallin in RPE. beta A3/A1-crystallin deficiency leads to clathrin-mediated epidermal growth factor receptor (EGFR) endocytosis abnormalities and actin network disruption at the apical side that result in RPE polarity disruption and degeneration. We found that beta A3/A1-crystallin binds to phosphatidylinositol transfer protein (PITP beta) and that beta A3/A1-crystallin deficiency diminishes phosphatidylinositol 4,5-biphosphate (PI(4,5)P-2), thus probably decreasing ezrin phosphorylation, EGFR activation, internalization, and degradation. We propose that beta A3/A1-crystallin acquired its RPE function before evolving as a structural element in the lens, and that in the RPE, it modulates the PI(4,5)P-2 pool through PITP beta /PLC signaling axis, coordinates EGFR activation, regulates ezrin phosphorylation and ultimately the cell polarity. Shang et al. utilize a conditional Cryba1 knockout mouse model to demonstrate a key role for beta A3/A1-crystallin in retinal pigmented epithelium. As a result of beta A3/A1-crystallin deficiency, the authors report EGFR endocytosis defects and actin network disruption which leads to polarity disruption and degeneration through PITP beta /PLC signaling.