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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 \u03b2A3\/A1-crystallin in RPE. \u03b2A3\/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 \u03b2A3\/A1-crystallin binds to phosphatidylinositol transfer protein (PITP\u03b2) and that \u03b2A3\/A1-crystallin deficiency diminishes phosphatidylinositol 4,5-biphosphate (PI(4,5)P<jats:sub>2<\/jats:sub>), thus probably decreasing ezrin phosphorylation, EGFR activation, internalization, and degradation. We propose that \u03b2A3\/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<jats:sub>2<\/jats:sub> pool through PITP\u03b2\/PLC signaling axis, coordinates EGFR activation, regulates ezrin phosphorylation and ultimately the cell polarity.<\/jats:p>","DOI":"10.1038\/s42003-021-02386-6","type":"journal-article","created":{"date-parts":[[2021,7,8]],"date-time":"2021-07-08T10:04:40Z","timestamp":1625738680000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["\u03b2A3\/A1-crystallin regulates apical polarity and EGFR endocytosis in retinal pigmented epithelial cells"],"prefix":"10.1038","volume":"4","author":[{"given":"Peng","family":"Shang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadezda","family":"Stepicheva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Teel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Austin","family":"McCauley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher Scott","family":"Fitting","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacey","family":"Hose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhonda","family":"Grebe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meysam","family":"Yazdankhah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayan","family":"Ghosh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3476-3888","authenticated-orcid":false,"given":"Anastasia","family":"Strizhakova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imran A.","family":"Bhutto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard A.","family":"Lutty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashwath","family":"Jayagopal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0476-3596","authenticated-orcid":false,"given":"Jiang","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4831-1153","authenticated-orcid":false,"given":"Jos\u00e9-Alain","family":"Sahel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"J.","family":"Samuel Zigler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James T.","family":"Handa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7204-6572","authenticated-orcid":false,"given":"Yuri","family":"Sergeev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raju V. 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