title: 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.affiliation: Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, PR China.
authors.forename: Chengchen
authors.initials: C
authors.lastname: Qin
authors.affiliation: Department of Biochemistry, College of Basic Medicine, Hubei University of Medicine, Hubei 442000, PR China.
authors.forename: Shan
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, PR China.
authors.forename: Qiujin
authors.initials: Q
authors.lastname: Yan
authors.affiliation: Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, PR China.
authors.forename: Xiuling
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, PR China.
authors.forename: Yatang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, PR China.
authors.forename: Mengxin
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, PR China; Hubei Province Key Laboratory of Allergy and Immunology, PR China. Electronic address: zhufan@hotmail.com.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhu
mesh_terms: D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D045744:Cell Line, Tumor; D020077:Endogenous Retroviruses / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D012694:Serine; D015398:Signal Transduction
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D012694:Serine; C579455:BDNF protein, human; D000071679:Glycogen Synthase Kinase 3 beta
keywords: BDNF; GSK3β; HERV-W; Schizophrenia