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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:p>Cataract is a leading ocular disease causing global blindness. The mechanism of cataractogenesis has not been well defined. Here, we demonstrate that the heat shock protein 90\u03b2 (HSP90\u03b2) plays a fundamental role in suppressing cataractogenesis. HSP90\u03b2 is the most dominant HSP in normal lens, and its constitutive high level of expression is largely derived from regulation by Sp1 family transcription factors. More importantly, HSP90\u03b2 is significantly down-regulated in human cataract patients and in aging mouse lenses, whereas HSP90\u03b2 silencing in zebrafish causes cataractogenesis, which can only be rescued by itself but not other HSP90 genes. Mechanistically, HSP90\u03b2 can directly interact with CHMP4B, a newly-found client protein involved in control of cytokinesis. HSP90\u03b2 silencing causes upregulation of CHMP4B and another client protein, the tumor suppressor p53. CHMP4B upregulation or overexpression induces excessive division of lens epithelial cells without proper differentiation. As a result, these cells were triggered to undergo apoptosis due to activation of the p53\/Bak\u2013Bim pathway, leading to cataractogenesis and microphthalmia. Silence of both HSP90\u03b2 and CHMP4B restored normal phenotype of zebrafish eye. 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