HSP90β prevents aging-related cataract formation through regulation of the charged multivesicular body protein (CHMP4B) and p53.
HSP90β prevents aging-related cataract formation through regulation of the charged multivesicular body protein (CHMP4B) and p53.
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DOI：
10.1073/pnas.2221522120
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发表时间：
2023-08
影响因子：
11.1
通讯作者：
Li, David Wan-Cheng
中科院分区：
文献类型：
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作者：
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
白内障是由基因突变、压力和衰老引起的蛋白质聚集引起的。受损的蛋白质聚集体被α-晶体蛋白结合，但由于其功能限制，不能回收到细胞质中。因此，维持晶状体的透明度需要真正的伴侣蛋白的功能。在这里，我们证明了热休克蛋白90β(HSP90β)作为眼内最重要的伴侣蛋白，在抑制白内障的发生中起着关键作用。热休克蛋白90β是晶状体中含量最丰富的伴侣蛋白，在白内障形成过程中表现出剧烈的变化。斑马鱼中热休克蛋白90β的沉默导致白内障，而其他热休克蛋白90基因无法挽救这一疾病。在机制上，HSP90β直接与CHMP4B相互作用，CHMP4B是一种新发现的客户蛋白，其上调促进过度增殖，并引发大量细胞凋亡，导致小眼炎和白内障的发生。白内障是导致全球失明的主要眼病。白内障的发生机制尚未很好地阐明。在此，我们证明了热休克蛋白90β(HSP90β)在抑制白内障发生中起着重要作用。热休克蛋白90β是正常晶状体中最主要的热休克蛋白，其结构性高水平表达在很大程度上源于Sp1家族转录因子的调控。更重要的是，在人类白内障患者和老化的小鼠晶状体中，热休克蛋白90β的表达显著下调，而斑马鱼中热休克蛋白90β的沉默会导致白内障的发生，这只能由自身来拯救，而不能通过其他热休克蛋白90基因来拯救。从机制上讲，HSP90β可以直接与CHMP4B相互作用，CHMP4B是一种新发现的参与胞质分裂控制的客户蛋白。热休克蛋白90β沉默导致CHMP4B和另一种客户蛋白，肿瘤抑制因子P53的上调。CHMP4B上调或过度表达会导致晶状体上皮细胞过度分裂而不能正常分化。结果，由于P53/Bak-Bim通路的激活，这些细胞被触发进行凋亡，导致白内障和小眼球。β和CHMP4B的沉默使斑马鱼的眼睛恢复了正常的表型。综上所述，我们的结果表明，热休克蛋白90CHMP4B通过负调控β和P53-Bak/Bim通路，是白内障发生的关键抑制因子。
Cataract is derived from protein aggregation due to genetic mutations, stress and aging. The damaged protein aggregates are bound by α-crystallins but cannot be recycled into cytoplasm due to their functional limitations. Thus, maintaining lens transparency requires functions of true chaperone proteins. Here, we demonstrate that heat shock protein 90β (HSP90β) acts as the most important chaperone in the ocular lens, and plays a critical role in suppressing cataractogenesis. HSP90β is the most abundant chaperone protein in lens and displays drastic change during cataractogenesis. HSP90β silencing in zebrafish causes cataract which cannot be rescued by other HSP90 genes. Mechanistically, HSP90β directly interacts with CHMP4B, a newly found client protein whose upregulation promotes excessive proliferation and also triggers massive apoptosis, leading to microphthalmia and cataractogenesis. 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.
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DOI：
10.1126/science.abk0410
发表时间：
2021-12-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gulluni F;Prever L;Li H;Krafcikova P;Corrado I;Lo WT;Margaria JP;Chen A;De Santis MC;Cnudde SJ;Fogerty J;Yuan A;Massarotti A;Sarijalo NT;Vadas O;Williams RL;Thelen M;Powell DR;Schueler M;Wiesener MS;Balla T;Baris HN;Tiosano D;McDermott BM Jr;Perkins BD;Ghigo A;Martini M;Haucke V;Boura E;Merlo GR;Buchner DA;Hirsch E
通讯作者：
Hirsch E
影响因子：
--
作者：
Datiles, Manuel B., III;Ansari, Rafat R.;Suh, Kwang I.;Vitale, Susan;Reed, George F.;Zigler, J. Samuel, Jr.;Ferris, Frederick L., III
通讯作者：
Ferris, Frederick L., III
影响因子：
5.3
作者：
BALER, R;DAHL, G;VOELLMY, R
通讯作者：
VOELLMY, R
影响因子：
3.4
作者：
JEDZINIAK, JA;KINOSHITA, JH;BENEDEK, GB
通讯作者：
BENEDEK, GB
影响因子：
64.8
作者：
Alexandrova EM;Yallowitz AR;Li D;Xu S;Schulz R;Proia DA;Lozano G;Dobbelstein M;Moll UM
通讯作者：
Moll UM