Glutaminyl cyclase inhibitor contributes to the regulation of HSP70, HSP90, actin, and ribosome on gene and protein levels in vitro
Glutaminyl cyclase inhibitor contributes to the regulation of HSP70, HSP90, actin, and ribosome on gene and protein levels in vitro
复制标题
谷氨酰胺酰环化酶抑制剂有助于体外调节 HSP70、HSP90、肌动蛋白和核糖体的基因和蛋白质水平
DOI：
10.1002/jcb.28222
复制
发表时间：
2019-06-01
影响因子：
4
通讯作者：
Wu, Haiqiang
中科院分区：
文献类型：
--
作者：
Yu, Xi;Li, Yue;Wu, Haiqiang
由于上调的谷氨酰胺环化酶(QC)在阿尔茨海默病(AD)的发生发展中起着关键作用，QC抑制剂被认为是治疗AD的疾病改良剂。基于体内显著的抗AD作用，已报道的化合物极大地支持了这一假说。为了更详细地阐明这一机制，首先在细胞系统中评估了一种选定的QC抑制剂(23)的作用。结果表明，23对PC12细胞的QC活性和焦谷氨酸修饰的淀粉样蛋白的生成均有明显的抑制作用。经RNA测序分析，处理细胞中共有13个和15个基因显著上调和下调。定量实时聚合酶链式反应、酶联免疫吸附试验、WB和免疫荧光分析结果支持23对PC12细胞转录组的影响。PC12细胞热休克蛋白(HSP)70和90的伴侣蛋白表达上调，而肌动蛋白基因表达和编码蛋白水平显著降低。此外，观察治疗后核糖体的变化。这些结果表明，23可以促进蛋白质的翻译、表达和折叠调节，并影响细胞骨架蛋白和其他蛋白质随后在细胞系统中的多价交联，这可能有助于理解QC抑制剂作为潜在的抗AD药物的机制。
Because of the crucial roles of upregulated glutaminyl cyclase (QC) in the initiation and development of Alzheimer's disease (AD), QC inhibitors are supposed as disease-modifying agents for the treatment of AD. And reported compounds encourage this hypothesis greatly based on the remarkable anti-AD effects in vivo. To illustrate the mechanism in detail, the actions of a selected QC inhibitor (23) were assessed firstly in a cell system here. It was demonstrated that QC activities and the generation of pyroglutamate-modified -amyloids in PC12 cells were both inhibited obviously after the treatment of 23. A total of 13 and 15 genes were up- and downregulated significantly in treated cells by RNA-sequencing analysis. Quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, WB, and immunoFLuorescence analysis supported the effects of 23 on the transcriptome of PC12 cells consequently. The expressions of chaperones, heat shock proteins (HSP) 70, and 90, were upreglutated, while gene expression of actin and the level of encoded protein were reduced significantly in PC12 cells with the treatment. Furthermore, the regulations of ribosome were observed after the treatment. These results indicate the potency of 23 to improve the translation, expression and folding regulation of proteins and affect the multivalent cross-linking of cytoskeletal protein and other proteins subsequently in the cell system and might contribute to the understanding of the mechanism of QC inhibitor as potential anti-AD agents.