Elevation of Ser9 phosphorylation of GSK3β is required for HERV-W env-mediated BDNF signaling in human U251 cells

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 3 beta (GSK3 beta). Both BDNF and GSK3 beta are schizophrenia-related genes. In this paper, we investigated whether GSK3 beta was involved in the HERV-W env-induced expression of BDNF. We found that HERV-W env increased phosphorylation of GSK3 beta at Ser9 (p-GSK3 beta (Ser9)) and the ratio of p-GSK3 beta (Ser9) to total GSK3 beta (p < 0.05) in U251 cells. Overexpression of HERV-W env led to a 36.2% reduction in GSK3 beta activity compared to control (p < 0.05). The levels of beta-catenin, cyclin D1 and TSC2 mRNAs were upregulated (p < 0.05). These data suggested that overexpression of HERV-W env might activate the GSK3 beta signaling pathway in U251 cells. Further, knockdown of GSK3 beta reduced the expression of total GSK3 beta, p-GSK3 beta (Ser9), and the ratio of p-GSK3 beta (Ser9) to total GSK3 beta by 28.6%, 50.4%, and 30.2%, respectively (p < 0.05). Levels of beta-catenin, cyclin D1 and TSC2 mRNAs were also reduced (p < 0.05). Interestingly, GSK3 beta activity increased (p < 0.05). Knockdown of GSK3 beta also decreased mRNA and protein expression of BDNF by 49.9% and 48.5% respectively (p < 0.05). These results indicated that phosphorylation of GSK3 beta 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). (C) 2016 Elsevier Ireland Ltd. All rights reserved.