NF-KappaB Activation by EBV
Explore and order pathway-specific siRNAs, real-time PCR assays, and expression vectors. View pathway information and literature references for your pathway.
  • Click on your proteins of interest in the pathway image or review below
  • Select your genes of interest and click "add selection"
  • When you have finished your gene selection, click "Find Products" to find assays, arrays, or create custom products
Download Image Terms of Use Download PPT
Pathway Navigator
NF-KappaB Activation by EBV
The EBV (Epstein-Barr Virus) is a member of the human herpes virus family, which infects greater than 90% of the world’s population. EBV is linked to the development of several malignancies, primarily of lymphoid and epithelial cell origin, including Burkitt’s lymphoma, post-transplant lymphoma, AIDS-associated lymphomas, Hodgkin’s disease, T-Cell lymphoma, NPC (Nasopharyngeal Carcinoma), parotid gland carcinoma, and gastric carcinoma. EBV-encoded RNAs (EBERs) are the most abundant viral transcripts in latently EBV-infected cells (Ref.1).

EBV primarily targets B-lymphocytes with the potential to produce indefinitely proliferating lymphocytes. Although primary infection is controlled principally by an antiviral T-Cell response, EBV persists by establishing a latent infection in memory B-lymphocytes. The viral oncoprotein LMP1 (Latent Membrane Protein-1) is essential for EBV-mediated lymphocyte transformation. LMP1 is expressed in most EBV-associated carcinomas and in Hodgkin’s lymphoma that constitutively transmits signals, activates NF-KappaB (Nuclear Factor-kappaB) and stimulates cell proliferation. The interaction of EBV glycoprotein GP350 with its cognate cellular receptor CD21 induces intracellular signaling from CD21, resulting in rapid activation of NF-KappaB (Ref.2). This receptor engagement induces specific tyrosine phosphorylation as well as activation of PKC (Protein Kinase-C), PI3K (Phosphatidylinositol 3-Kinase), and NF-KappaB. At later stages of infection, LMP1 is produced and inserted in the cellular membrane. LMP1 activates NF-KappaB by usurping the cytoplasmic TNF (Tumor Necrosis Factor) signaling pathway. The cytoplasmic tail of TNFR1 (TNF Receptor-1) interacts with the TRADD (TNFR-Associated Death Domain) protein, a signaling molecule with a similar death domain motif. Over expression of TRADD activates NF-KappaB and induces apoptosis, implicating it as an important mediator of TNF-Alpha signaling. TRADD also interacts with the TRAF2 (TNFR-Associated Factor-2) and with RIP (Receptor-Interacting Kinase), both of which activate NF-KappaB. NF-KappaB activation by the LMP1 signaling cascade is mediated through I-kappaB-Alpha (Inhibitor of Kappa Light Chain Gene Enhancer in B-Cells-Alpha) phosphorylation and degradation (Ref.3). Degradation of I-KappaB unmasks the nuclear localization signal of NF-KappaB, which then migrates to the nucleus and activates transcription along with RNA Pol-II (RNA Polymerase) and TBP (TATA Binding Protein). The interactions of LMP1 with TRAFs, TRADD, or RIP activate a kinase cascade that includes NIK (NF-KappaB-Inducing Kinase) and the IKK (I-KappaB Kinases) complex. Two domains, CTAR1 and CTAR2 (C-Terminal Activator Regions), within the cytoplasmic carboxy terminus of LMP1 also activate the NF-KappaB transcription factor. The membrane proximal domain, CTAR1, interacts with the cellular molecules that mediate signals from the TNFR including CD40. These molecules, entitled TRAFs, form heteromeric complexes that transduce signals depending on the receptor and may activate NF-KappaB, induce cellular growth, or induce apoptosis. TRAF1, TRAF2, and TRAF3 assemble on the TRAF interacting domain in CTAR1, while the TRAF adaptor proteins, TRADD and RIP, bind to CTAR2 (Ref.4). In addition, CTAR1 but not CTAR2 induces expression of cell genes such as TRAF1 and the EGFR while CTAR2 uniquely activate JNK1 (c-Jun N-terminal kinase) and SEK1 (SAPK/ERK Kinase-1) resulting in activation of transcription factors c-Jun and c-Fos. Moreover, LMP1 also activates p38 and the downstream transcription factor ATF2 (Activating Transcription Factor-2).

LMP1 is also associated with the upregulation and activation of markers (CD23 and CD40), and cell adhesion molecules (ICAM1) in EBV-transformed B-lymphocytes. In addition to its effects on cell proliferation, LMP1 prevents apoptosis in a variety of settings. In resting B-lymphocytes, LMP1 provides a trophic signal, thus blocking cell death following BCR (B-Cell Receptor) engagement. LMP1 also induces antiapoptotic proteins such as Bcl2 (B-Cell CLL/Lymphoma-2), Mcl1, A20, and TRAF1 (Ref.5) and can protect cells from serum starvation, etoposide, and p53-induced apoptosis. In addition to GP350, the EBV protein LMP1 is able to trigger the production of some cytokines such as IL-6, IL-8, and IL-10. EBNA2 (EBV Nuclear Antigen-2), a DNA-binding protein required for B-lymphocyte immortalization, induces Ifn-Alpha/Ifn-Beta expression in Burkitts lymphoma cell lines.

EBV infection is highly prevalent worldwide, and in most patients it is asymptomatic. Occasionally, primary exposure to EBV results in infectious mononucleosis (Ref.6). The virus is generally spread to and between young children through salivary contact, and only causes clinical illness where primary infection is delayed until adolescence or beyond, when an intense immunopathological reaction leads to the symptoms of infectious mononucleosis in roughly 50% of cases. More than 90% of the world’s population carries EBV as a life-long, latent infection of B-lymphocytes. Most HIV (Human Immunodeficiency Virus)-infected people are persistently infected with EBV, and with progressive immunodeficiency numbers of EBV infected B-Cells in the circulation increase and opportunistic lymphomas may develop. In addition to lymphomas, EBV is also associated with OHL (Oral Hairy Leukoplakia), which is common in late HIV infection (Ref.7).