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

Abstract

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).

• Authors: Chengchen Qin, Shan Li, Qiujin Yan, Xiuling Wang, Yatang Chen, Ping Zhou, Mengxin Lu, Fan Zhu
• Journal: Neuroscience letters (Neurosci Lett) Vol. 627 Pg. 84-91 (08 03 2016) ISSN: 1872-7972 [Electronic] Ireland
• PMID: 27235578 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Brain-Derived Neurotrophic Factor
• RNA, Messenger
• Serine
• BDNF protein, human
• Glycogen Synthase Kinase 3 beta

Topics

• Brain-Derived Neurotrophic Factor (metabolism)
• Cell Line, Tumor
• Endogenous Retroviruses (metabolism)
• Gene Knockdown Techniques
• Glycogen Synthase Kinase 3 beta (genetics, metabolism)
• Humans
• Phosphorylation
• RNA, Messenger (metabolism)
• Serine
• Signal Transduction