salubrinal and Lymphoma

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.

Topics: Carcinogens; Cell Line; Cinnamates; Endoplasmic Reticulum Stress; Enzyme Inhibitors; Epstein-Barr Virus Infections; Eukaryotic Initiation Factor-2; Gene Expression Profiling; Gene Expression Regulation, Viral; Genes, Immediate-Early; Germinal Center; Herpesvirus 4, Human; Humans; Immediate-Early Proteins; Lymphocytes; Lymphoma; Membrane Glycoproteins; Plasma Cells; Tetradecanoylphorbol Acetate; Thapsigargin; Thiourea; Trans-Activators; Viral Matrix Proteins; Virus Replication