title: Proteomics reveal energy metabolism and mitogen-activated protein kinase signal transduction perturbation in human Borna disease virus Hu-H1-infected oligodendroglial cells.
abstract: Borna disease virus (BDV) is a neurotropic, non-cytolytic RNA virus which replicates in the cell nucleus targeting mainly hippocampal neurons, but also astroglial and oligodendroglial cells in the brain. BDV is associated with a large spectrum of neuropsychiatric pathologies in animals. Its relationship to human neuropsychiatric illness still remains controversial. We could recently demonstrate that human BDV strain Hu-H1 promoted apoptosis and inhibited cell proliferation in a human oligodendroglial cell line (OL cells) whereas laboratory BDV strain V acted contrariwise. Here, differential protein expression between BDV Hu-H1-infected OL cells and non-infected OL cells was assessed through a proteomics approach, using two-dimensional electrophoresis followed by matrix-assisted laser desorption ionization-time of flight tandem mass spectrometry. A total of 63 differential host proteins were identified in BDV Hu-H1-infected OL cells compared to non-infected OL cells. We found that most changes referred to alterations related to the pentose phosphate pathway, glyoxylate and dicarboxylate metabolism, the tricarboxylic acid (TCA) cycle, and glycolysis /gluconeogenesis. By manual querying, two differential proteins were found to be associated with mitogen-activated protein kinase (MAPK) signal transduction. Five key signaling proteins of this pathway (i.e., p-Raf, p-MEK, p-ERK1/2, p-RSK, and p-MSK) were selected for Western blotting validation. p-ERK1/2 and p-RSK were found to be significantly up-regulated, and p-MSK was found to be significantly down-regulated in BDV Hu-H1-infected OL cells compared to non-infected OL cell. Although BDV Hu-H1 constitutively activated the ERK-RSK pathway, host cell proliferation and nuclear translocation of activated pERK in BDV Hu-H1-infected OL cells were impaired. These findings indicate that BDV Hu-H1 infection of human oligodendroglial cells significantly perturbs host energy metabolism, activates the downstream ERK-RSK complex of the Raf/MEK/ERK signaling cascade, and disturbs host cell proliferation possibly through impaired nuclear translocation of pERK, a finding which warrants further research.
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China; Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China; Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China; Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
authors.forename: M
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Bornavirus Research Group affiliated to the Free University of Berlin, Berlin, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Bode
authors.affiliation: Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China; Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China; Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
authors.forename: J
authors.initials: J
authors.lastname: Pan
authors.affiliation: Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China; Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
authors.forename: L
authors.initials: L
authors.lastname: Lv
authors.affiliation: Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China; Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China; Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China; Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China; Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China; Institute of Neuroscience, Chongqing Medical University, Chongqing, China; Department of Rehabilitation, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: R
authors.initials: R
authors.lastname: Huang
authors.affiliation: Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China; Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China; Institute of Neuroscience, Chongqing Medical University, Chongqing, China. Electronic address: xiepeng@cqmu.edu.cn.
authors.forename: P
authors.initials: P
authors.lastname: Xie
mesh_terms: D021581:Active Transport, Cell Nucleus; D015153:Blotting, Western; D001891:Borna disease virus / Q000502:physiology*; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D015180:Electrophoresis, Gel, Two-Dimensional; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology* / Q000821:virology*; D040901:Proteomics / Q000379:methods
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; C113580:U 0126; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: BDV; Borna disease virus; ERK signaling; energy; oligodendroglial cell; proteomic