title: Endoplasmic reticulum stress causes EBV lytic replication.
abstract: Endoplasmic reticulum (ER) stress triggers a homeostatic cellular response in mammalian cells to ensure efficient folding, sorting, and processing of client proteins. In lytic-permissive lymphoblastoid cell lines (LCLs), pulse exposure to the chemical ER-stress inducer thapsigargin (TG) followed by recovery resulted in the activation of the EBV immediate-early (BRLF1, BZLF1), early (BMRF1), and late (gp350) genes, gp350 surface expression, and virus release. The protein phosphatase 1 a (PP1a)-specific phosphatase inhibitor Salubrinal (SAL) synergized with TG to induce EBV lytic genes; however, TG treatment alone was sufficient to activate EBV lytic replication. SAL showed ER-stress-dependent and -independent antiviral effects, preventing virus release in human LCLs and abrogating gp350 expression in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated B95-8 cells. TG resulted in sustained BCL6 but not BLIMP1 or CD138 expression, which is consistent with maintenance of a germinal center B-cell, rather than plasma-cell, phenotype. Microarray analysis identified candidate genes governing lytic replication in LCLs undergoing ER stress.
authors.affiliation: Department of Pathology, University of Pittsburgh and Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Gwen Marie
authors.initials: GM
authors.lastname: Taylor
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Raghuwanshi
authors.forename: David T
authors.initials: DT
authors.lastname: Rowe
authors.forename: Robert M
authors.initials: RM
authors.lastname: Wadowsky
authors.forename: Adam
authors.initials: A
authors.lastname: Rosendorff
mesh_terms: D002273:Carcinogens / Q000494:pharmacology; D002460:Cell Line; D002934:Cinnamates / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020031:Epstein-Barr Virus Infections / Q000378:metabolism / Q000503:physiopathology / Q000821:virology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D020869:Gene Expression Profiling; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D017781:Genes, Immediate-Early / Q000235:genetics; D018858:Germinal Center / Q000166:cytology / Q000378:metabolism / Q000821:virology; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology; D008223:Lymphoma / Q000378:metabolism / Q000821:virology*; D008562:Membrane Glycoproteins / Q000235:genetics; D010950:Plasma Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics; D014763:Viral Matrix Proteins / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
chemical_list: C068382:BRLF1 protein, Human herpesvirus 4; C063676:BZLF1 protein, Herpesvirus 4, Human; D002273:Carcinogens; D002934:Cinnamates; D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2; C034059:GP 300-350, Epstein-Barr virus; D017874:Immediate-Early Proteins; D008562:Membrane Glycoproteins; D015534:Trans-Activators; D014763:Viral Matrix Proteins; C496827:salubrinal; D019284:Thapsigargin; D013890:Thiourea; D013755:Tetradecanoylphorbol Acetate