O-GlcNAcylation regulates ischemia-induced neuronal apoptosis through AKT signaling.
O-GlcNAcylation regulates ischemia-induced neuronal apoptosis through AKT signaling.
复制标题
DOI：
10.1038/srep14500
复制
发表时间：
2015-09-28
影响因子：
4.6
通讯作者：
Gong CX
中科院分区：
文献类型：
--
作者：
Shi J;Gu JH;Dai CL;Gu J;Jin X;Sun J;Iqbal K;Liu F;Gong CX
细胞凋亡在神经发育和神经系统疾病中起重要作用。在这项研究中，我们发现O-GlcNAc化，一种独特的蛋白质翻译后修饰与O-连接的β-N-乙酰葡萄糖胺（GlcNAc），通过减弱AKT和Bad的磷酸化/激活促进细胞凋亡。通过使用免疫共沉淀和诱变技术，我们确定了O-GlcNAc修饰在AKT的Thr 308和Ser 473。O-GlcNAc化诱导的细胞凋亡被AKT的过表达减弱。我们还发现，蛋白质O-GlcNAcylation在脑缺血的前4小时内动态升高，随后在大脑中动脉闭塞（MCAO）后持续下降。O-GlcNAc化水平的升高与细胞凋亡的激活相一致。最后，我们发现缺血脑组织中AKT磷酸化和O-GlcNAc化之间呈负相关。这些结果表明，脑缺血诱导O-GlcNAc化的快速增加，其通过下调AKT活性促进细胞凋亡。这些发现提供了一种新的机制，通过O-GlcNAc酰化调节缺血诱导的神经元凋亡，通过AKT信号。
Apoptosis plays an important role in neural development and neurological disorders. In this study, we found that O-GlcNAcylation, a unique protein posttranslational modification with O-linked β-N-acetylglucosamine (GlcNAc), promoted apoptosis through attenuating phosphorylation/activation of AKT and Bad. By using co-immunoprecipitation and mutagenesis techniques, we identified O-GlcNAc modification at both Thr308 and Ser473 of AKT. O-GlcNAcylation-induced apoptosis was attenuated by over-expression of AKT. We also found a dynamic elevation of protein O-GlcNAcylation during the first four hours of cerebral ischemia, followed by continuous decline after middle cerebral artery occlusion (MCAO) in the mouse brain. The elevation of O-GlcNAcylation coincided with activation of cell apoptosis. Finally, we found a negative correlation between AKT phosphorylation and O-GlcNAcylation in ischemic brain tissue. These results indicate that cerebral ischemia induces a rapid increase of O-GlcNAcylation that promotes apoptosis through down-regulation of AKT activity. These findings provide a novel mechanism through which O-GlcNAcylation regulates ischemia-induced neuronal apoptosis through AKT signaling.