βA3/A1-crystallin regulates apical polarity and EGFR endocytosis in retinal pigmented epithelial cells
Peng Shang, Nadezda A. Stepicheva, Kenneth Teel, Austin McCauley, Christopher Scott Fitting, Stacey Hose, Rhonda Grebe, Meysam Yazdankhah, Sayan Ghosh, Haitao Liu, Anastasia Strizhakova, Joseph Weiss, Imran Ahmed Bhutto, Gerard A. Lutty, Ashwath Jayagopal, Jiang Qian, José‐Alain Sahel, J. Samuel Zigler, James T. Handa, Yuri V. Sergeev, Raju V. S. Rajala, Simon C. Watkins, Debasish Sinha
Abstract
Abstract 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 βA3/A1-crystallin in RPE. βA3/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 βA3/A1-crystallin binds to phosphatidylinositol transfer protein (PITPβ) and that βA3/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 βA3/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 PITPβ/PLC signaling axis, coordinates EGFR activation, regulates ezrin phosphorylation and ultimately the cell polarity.