Elevation of Ser9 phosphorylation of GSK3 beta is required for HERV-W env-mediated BDNF signaling in human U251 cells
Elevation of Ser9 phosphorylation of GSK3 beta is required for HERV-W env-mediated BDNF signaling in human U251 cells
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人 U251 细胞中 HERV-W env 介导的 BDNF 信号传导需要 GSK3 beta Ser9 磷酸化的升高
DOI：
10.1016/j.neulet.2016.05.036
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发表时间：
2016
影响因子：
2.5
通讯作者：
通讯作者）
中科院分区：
文献类型：
--
作者：
Qin Chengchen;Li Shan;Yan Qiujin;Wang Xiuling;Chen Yatang;Zhou Ping;Lu Mengxin;Zhu Fan（朱帆;通讯作者）
人类内源性逆转录病毒W家族（HERV-W）包膜（env）已知与神经和精神疾病有关，如多发性硬化症和精神分裂症。既往研究表明，HERV-W env过表达可诱导脑源性神经营养因子（BDNF）基因表达。在人和大鼠细胞中，bdnf介导的信号转导可能受到糖原合成酶激酶3β (GSK3β)的调节。BDNF和GSK3β都是精神分裂症相关基因。在本文中，我们研究GSK3β是否参与HERV-W env诱导的BDNF表达。我们发现HERV-W env增加了U251细胞中GSK3β Ser9位点的磷酸化（p-GSK3β (Ser9)）和p-GSK3β (Ser9)与总GSK3β的比值（p < 0.05）。与对照组相比，HERV-W env过表达导致GSK3β活性降低36.2% （p < 0.05）。β-catenin、cyclin D1、TSC2 mrna水平上调（p < 0.05）。这些数据表明HERV-W env的过表达可能激活了U251细胞中的GSK3β信号通路。此外，GSK3β的敲低使总GSK3β、p-GSK3β (Ser9)的表达以及p-GSK3β (Ser9)与总GSK3β的比值分别降低28.6%、50.4%和30.2% （p < 0.05）。β-catenin、cyclin D1和TSC2 mrna水平也降低（p < 0.05）。有趣的是，GSK3β活性升高（p < 0.05）。GSK3β敲低BDNF mRNA和蛋白表达量分别降低49.9%和48.5% （p < 0.05）。这些结果表明，GSK3β Ser9位点的磷酸化可能参与了HERV-W env诱导的BDNF表达，并有望提高我们对HERV-W env在神经和精神疾病（精神分裂症等）中的作用的认识。
Human endogenous retrovirus W family (HERV-W) envelope (env) is known to be associated with neurological and psychiatric disorders, such as multiple sclerosis and schizophrenia. Previous studies showed that overexpression of HERV-W env could induce brain-derived neurotrophic factor (BDNF) gene expression. In human and rat cells, BDNF-mediated signal transduction might be modulated by glycogen synthase kinase 3β (GSK3β). Both BDNF and GSK3β are schizophrenia-related genes. In this paper, we investigated whether GSK3β was involved in the HERV-W env-induced expression of BDNF. We found that HERV-W env increased phosphorylation of GSK3β at Ser9 (p-GSK3β (Ser9)) and the ratio of p-GSK3β (Ser9) to total GSK3β (p < 0.05) in U251 cells. Overexpression of HERV-W env led to a 36.2% reduction in GSK3β activity compared to control (p < 0.05). The levels of β-catenin, cyclin D1 and TSC2 mRNAs were upregulated (p < 0.05). These data suggested that overexpression of HERV-W env might activate the GSK3β signaling pathway in U251 cells. Further, knockdown of GSK3β reduced the expression of total GSK3β, p-GSK3β (Ser9), and the ratio of p-GSK3β (Ser9) to total GSK3β by 28.6%, 50.4%, and 30.2%, respectively (p < 0.05). Levels of β-catenin, cyclin D1 and TSC2 mRNAs were also reduced (p < 0.05). Interestingly, GSK3β activity increased (p < 0.05). Knockdown of GSK3β also decreased mRNA and protein expression of BDNF by 49.9% and 48.5% respectively (p < 0.05). These results indicated that phosphorylation of GSK3β at Ser9 might be involved in HERV-W env-induced BDNF expression, and will hopefully improve our understanding of the role of HERV-W env in neurological and psychiatric diseases (schizophrenia, etc).