HSP90 prevents aging- related cataract formation through regulation of the charged multivesicular body protein (CHMP4B) and p53

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 beta (HSP90 beta) plays a fundamental role in suppressing cataractogenesis. HSP90 beta 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 beta is significantly down-regulated in human cataract patients and in aging mouse lenses, whereas HSP90 beta silencing in zebrafish causes cataractogenesis, which can only be rescued by itself but not other HSP90 genes. Mechanistically, HSP90 beta can directly interact with CHMP4B, a newly-found client protein involved in control of cytokinesis. HSP90 beta 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-Bim pathway, leading to cataractogenesis and microphthalmia. Silence of both HSP90 beta and CHMP4B restored normal phenotype of zebrafish eye. Together, our results reveal that HSP90 beta is a critical inhibitor of cataractogenesis through negative regulation of CHMP4B and the p53-Bak/ Bim pathway.