EBV latency III immortalization program sensitizes B cells to induction of CD95-mediated apoptosis via LMP1: role of NF-kappaB, STAT1, and p53

Blood. 2006 Mar 1;107(5):2070-8. doi: 10.1182/blood-2005-05-2053. Epub 2005 Nov 29.

Abstract

Epstein-Barr virus (EBV) induces CD95 expression and the CD95 gene (FAS) is regulated by NF-kappaB, STAT1, and/or p53. To understand the contribution of these factors in the regulation of CD95 by EBV in lymphoblastoid cell lines (LCLs), we cloned dominant-active IkappaBalpha, active (STAT1alpha) and inactive (STAT1beta) forms of STAT1, p53, a dominant-negative mutant of LMP1, and wild-type LMP1 into a novel double-inducible episomal vector, pRT-1. These plasmids were stably transfected either into wild-type LCLs or EREB2-5 cells, an LCL with an estrogen-regulatable EBNA2 protein. Inhibition of LMP1 signaling decreased expression of CD95, whereas overexpression of LMP1 markedly increased it. Induction of the latency III program in EREB2-5 cells correlated with activation of NF-kappaB, STAT1, and p53. CD95 expression was regulated by these 3 transcriptional systems. STAT1 and p53 activation were secondary to NF-kappaB activation. CD95 surface expression sensitized EBV-infected B cells to the induction of CD95-mediated apoptosis. In vitro inhibition of CD95-CD95 ligand interaction was found to reverse T-cell killing of EBV-infected B cells. Therefore, LMP1 activation of NF-kappaB sensitizes infected B cells to CD95-mediated apoptosis and renders EBV latency III-immortalized B cells susceptible to elimination by the immune system, contributing to the establishment of a host/virus equilibrium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Apoptosis* / genetics
  • B-Lymphocytes / metabolism*
  • B-Lymphocytes / virology
  • Cell Line, Tumor
  • Cell Transformation, Viral* / drug effects
  • Cell Transformation, Viral* / genetics
  • Epstein-Barr Virus Infections / genetics
  • Epstein-Barr Virus Infections / metabolism*
  • Epstein-Barr Virus Infections / virology
  • Epstein-Barr Virus Nuclear Antigens / genetics
  • Epstein-Barr Virus Nuclear Antigens / metabolism
  • Estrogens / pharmacology
  • Fas Ligand Protein
  • Gene Expression Regulation / drug effects
  • Genes, Dominant / genetics
  • Genetic Vectors / metabolism
  • Herpesvirus 4, Human / metabolism*
  • Humans
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Interferon-Stimulated Gene Factor 3 / genetics
  • Interferon-Stimulated Gene Factor 3 / metabolism
  • Membrane Glycoproteins / metabolism
  • Mutation
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism
  • Plasmids / genetics
  • Plasmids / metabolism
  • Signal Transduction* / drug effects
  • Signal Transduction* / genetics
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / virology
  • Tumor Necrosis Factors / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Viral Matrix Proteins / genetics
  • Viral Matrix Proteins / metabolism
  • Viral Proteins
  • fas Receptor / biosynthesis

Substances

  • EBNA-2 protein, Human herpesvirus 4
  • EBV-associated membrane antigen, Epstein-Barr virus
  • Epstein-Barr Virus Nuclear Antigens
  • Estrogens
  • FASLG protein, human
  • Fas Ligand Protein
  • I-kappa B Proteins
  • Interferon-Stimulated Gene Factor 3
  • Membrane Glycoproteins
  • NF-kappa B
  • NFKBIA protein, human
  • Tumor Necrosis Factors
  • Tumor Suppressor Protein p53
  • Viral Matrix Proteins
  • Viral Proteins
  • fas Receptor
  • gamma interferon activation factor
  • NF-KappaB Inhibitor alpha