HSP90β prevents aging-related cataract formation through regulation of the charged multivesicular body protein (CHMP4B) and p53

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 31; p. e2221522120
• Main Authors: Fu, Jia-Ling, Zheng, Shu-Yu, Wang, Yan, Hu, Xue-Bin, Xiao, Yuan, Wang, Jing-Miao, Zhang, Lan, Wang, Ling, Nie, Qian, Hou, Min, Bai, Yue-Yue, Gan, Yu-Wen, Liang, Xing-Miao, Xie, Liu-Liu, Li, David Wan-Cheng
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 01.08.2023
• Subjects: Aging; Aging - genetics; Animals; Apoptosis; BIM protein; Biological Sciences; Cataract - genetics; Cataracts; Cell differentiation; Cytokinesis; Danio rerio; Endosomal Sorting Complexes Required for Transport - metabolism; Epithelial cells; Epithelium; Eye diseases; Gene regulation; Heat shock proteins; HSP90 Heat-Shock Proteins - metabolism; Hsp90 protein; Humans; Lenses; Mice; Microphthalmia; Multivesicular Bodies - metabolism; p53 Protein; Phenotypes; Proteins; Transcription factors; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Zebrafish; Zebrafish - genetics; Zebrafish - metabolism; CHMP4B; cataract; lens; HSP90β; p53
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2221522120

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 90β (HSP90β) plays a fundamental role in suppressing cataractogenesis. HSP90β 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, HSP90β is significantly down-regulated in human cataract patients and in aging mouse lenses, whereas HSP90β silencing in zebrafish causes cataractogenesis, which can only be rescued by itself but not other HSP90 genes. Mechanistically, HSP90β can directly interact with CHMP4B, a newly-found client protein involved in control of cytokinesis. HSP90β 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 HSP90β and CHMP4B restored normal phenotype of zebrafish eye. Together, our results reveal that HSP90β is a critical inhibitor of cataractogenesis through negative regulation of CHMP4B and the p53-Bak/Bim pathway.