CBP/p300 Bromodomains Regulate Amyloid-like Protein Aggregation upon Aberrant Lysine Acetylation.
CBP/p300 Bromodomains Regulate Amyloid-like Protein Aggregation upon Aberrant Lysine Acetylation.
复制标题
CBP/p300溴化构域在异常赖氨酸乙酰化后调节淀粉样淀粉样蛋白样蛋白聚集。
DOI：
10.1016/j.chembiol.2016.11.009
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发表时间：
2017-01-19
影响因子：
8.6
通讯作者：
La Thangue NB
中科院分区：
文献类型：
--
作者：
Olzscha H;Fedorov O;Kessler BM;Knapp S;La Thangue NB
赖氨酸乙酰化越来越被认为是细胞内稳态的一般生物学原理，并且在不同的人类病理中受到异常控制。在这里，我们描述了一个全球性的影响淀粉样蛋白聚集在人类细胞中，结果从异常赖氨酸乙酰化。布罗莫结构域阅读器蛋白参与聚集过程，并且使用化学生物学和基因沉默，我们确定p300/CBP布罗莫结构域是聚集发生所必需的。此外，蛋白质聚集通过损害泛素蛋白酶体系统（UPS）和蛋白质翻译来扰乱蛋白质稳态，导致细胞活力降低。p300/CBP布罗莫结构域抑制剂阻止聚集，这与增强的UPS功能和增加的细胞活力一致。亨廷顿蛋白的病理相关形式的聚集类似地受到p300/CBP抑制的影响。我们的研究结果对理解蛋白质聚集的分子基础具有意义，并强调了用基于溴结构域的策略治疗淀粉样蛋白样病变和相关蛋白质折叠疾病的可能性。异常乙酰化导致淀粉样蛋白聚集并扰乱蛋白质稳态p300/CBP布罗莫结构域蛋白参与蛋白质聚集p300/CBP布罗莫结构域抑制剂逆转细胞毒性并恢复蛋白质稳态布罗莫结构域抑制剂也减少病理性亨廷顿蛋白聚集Olzscha et al.证明异常乙酰化的蛋白质在人类细胞中形成淀粉样聚集体。用小分子抑制剂抑制p300/CBP布罗莫结构域可逆转聚集诱导的细胞毒性。由病理性延长的亨廷顿蛋白引起的聚集体也以类似的方式表现。
Lysine acetylation is becoming increasingly recognized as a general biological principle in cellular homeostasis, and is subject to abnormal control in different human pathologies. Here, we describe a global effect on amyloid-like protein aggregation in human cells that results from aberrant lysine acetylation. Bromodomain reader proteins are involved in the aggregation process and, using chemical biology and gene silencing, we establish that p300/CBP bromodomains are necessary for aggregation to occur. Moreover, protein aggregation disturbs proteostasis by impairing the ubiquitin proteasome system (UPS) and protein translation, resulting in decreased cell viability. p300/CBP bromodomain inhibitors impede aggregation, which coincides with enhanced UPS function and increased cell viability. Aggregation of a pathologically relevant form of huntingtin protein is similarly affected by p300/CBP inhibition. Our results have implications for understanding the molecular basis of protein aggregation, and highlight the possibility of treating amyloid-like pathologies and related protein folding diseases with bromodomain inhibitor-based strategies. Aberrant acetylation causes amyloid-like aggregation and disturbs proteostasis p300/CBP bromodomain proteins are involved in the protein aggregation p300/CBP bromodomain inhibitors reverse the cytotoxicity and restore proteostasis Bromodomain inhibitors also decrease pathological huntingtin protein aggregation Olzscha et al. demonstrate that aberrantly acetylated proteins form amyloid-like aggregates in human cells. Inhibition of the p300/CBP bromodomains with small-molecule inhibitors reverses the aggregation-induced cytotoxicity. Aggregates caused by a pathologically elongated huntingtin behave in a similar way.