Role of NF-kappa B in cell survival and transcription of latent membrane protein 1-expressing or Epstein-Barr virus latency III-infected cells.

in Journal of virology by Ellen D Cahir-McFarland, Kara Carter, Andreas Rosenwald, Jena M Giltnane, Sarah E Henrickson, Louis M Staudt, Elliott Kieff

TLDR

  • The study investigates how a protein called NF-kappa B affects the way cells respond to a virus called EBV. The study found that NF-kappa B plays a crucial role in regulating the way cells respond to EBV. The study also identified new genes that are affected by NF-kappa B and how they are involved in cell migration, antigen presentation, and other processes.

Abstract

Epstein-Barr virus (EBV) latency III infection converts B lymphocytes into lymphoblastoid cell lines (LCLs) by expressing EBV nuclear and membrane proteins, EBNAs, and latent membrane proteins (LMPs), which regulate transcription through Notch and tumor necrosis factor receptor pathways. The role of NF-kappa B in LMP1 and overall EBV latency III transcriptional effects was investigated by treating LCLs with BAY11-7082 (BAY11). BAY11 rapidly and irreversibly inhibited NF-kappa B, decreased mitochondrial membrane potential, induced apoptosis, and altered LCL gene expression. BAY11 effects were similar to those of an NF-kappa B inhibitor, Delta N-I kappa B alpha, in effecting decreased JNK1 expression and in microarray analyses. More than 80% of array elements that decreased with Delta N-I kappa B alpha expression decreased with BAY11 treatment. Newly identified NF-kappa B-induced, LMP1-induced, and EBV-induced genes included pleckstrin, Jun-B, c-FLIP, CIP4, and I kappa B epsilon. Of 776 significantly changed array elements, 134 were fourfold upregulated in EBV latency III, and 74 were fourfold upregulated with LMP1 expression alone, whereas only 28 were more than fourfold downregulated by EBV latency III. EBV latency III-regulated gene products mediate cell migration (EBI2, CCR7, RGS1, RANTES, MIP1 alpha, MIP1 beta, CXCR5, and RGS13), antigen presentation (major histocompatibility complex proteins and JAW1), mitogen-activated protein kinase pathway (DUSP5 and p62Dok), and interferon (IFN) signaling (IFN-gamma R alpha, IRF-4, and STAT1). Comparison of EBV latency III LCL gene expression to immunoglobulin M (IgM)-stimulated B cells, germinal-center B cells, and germinal-center-derived lymphomas clustered LCLs with IgM-stimulated B cells separately from germinal-center cells or germinal-center lymphoma cells. Expression of IRF-2, AIM1, ASK1, SNF2L2, and components of IFN signaling pathways further distinguished EBV latency III-infected B cells from IgM-stimulated or germinal-center B cells.

Overview

  • The study investigates the role of NF-kappa B in EBV latency III transcriptional effects by treating LCLs with BAY11-7082 (BAY11).
  • The study compares the outcomes observed under different experimental conditions or interventions, including BAY11 and an NF-kappa B inhibitor, Delta N-I kappa B alpha, in effecting decreased JNK1 expression and in microarray analyses. More than 80% of array elements that decreased with Delta N-I kappa B alpha expression decreased with BAY11 treatment.

Comparative Analysis & Findings

  • BAY11 rapidly and irreversibly inhibited NF-kappa B, decreased mitochondrial membrane potential, induced apoptosis, and altered LCL gene expression. BAY11 effects were similar to those of an NF-kappa B inhibitor, Delta N-I kappa B alpha, in effecting decreased JNK1 expression and in microarray analyses. More than 80% of array elements that decreased with Delta N-I kappa B alpha expression decreased with BAY11 treatment.

Implications and Future Directions

  • The study's findings suggest that NF-kappa B plays a crucial role in EBV latency III transcriptional effects. The study identifies newly identified NF-kappa B-induced, LMP1-induced, and EBV-induced genes, including pleckstrin, Jun-B, c-FLIP, CIP4, and I kappa B epsilon. The study also highlights the importance of NF-kappa B in regulating cell migration, antigen presentation, mitogen-activated protein kinase pathway, and interferon signaling. Future research directions could explore the role of NF-kappa B in EBV-associated diseases and the potential of NF-kappa B inhibitors as therapeutic agents.
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