Abstract
The principal Epstein-Barr virus (EBV) oncoprotein, Latent Membrane Protein 1 (LMP1), is expressed in most EBV-associated human malignancies. LMP1 mimics CD40 receptor signaling to provide infected cells with constitutive NF-κB, MAP kinase, IRF7, and PI3 kinase pathway stimulation. EBV-transformed B-cells are particularly dependent on constitutive NF-κB activity, and rapidly undergo apoptosis upon NF-κB blockade. Here, we review LMP1 function, with special attention to current understanding of the molecular mechanisms of LMP1-mediated NF-κB and IRF7 pathway activation. Recent advances include the elucidation of transmembrane motifs important for LMP1 trafficking and ligand-independent signaling, analysis of genome-wide LMP1 gene targets, and the identification of novel cell proteins that mediate LMP1 NF-κB and IRF7 pathway activation.
Highlights
Epstein-Barr virus (EBV) is a gamma-herpesvirus that infects >90% of people worldwide, is the etiologic agent of infectious mononucleosis, and is associated with multiple human malignancies.Upon primary infection, EBV initially infects and may replicate in oropharyngeal epithelial cells [1,2].EBV gains access to the B-cell compartment, where it drives robust B-cell proliferation through expression of six EBV nuclear antigens, multiple non-coding RNAs, and two integral membrane proteins, Latent Membrane Protein 1 (LMP1) and LMP2A [3,4]
Transgenic LMP1 expression in murine models promotes the development of B-cell lymphomas and carcinomas [8,9,10,11]
While latent EBV infection is detectable in roughly 10% of gastric carcinomas worldwide, only a subset appear to express LMP1 [22]
Summary
Epstein-Barr virus (EBV) is a gamma-herpesvirus that infects >90% of people worldwide, is the etiologic agent of infectious mononucleosis, and is associated with multiple human malignancies. Infected cells enter lymph node germinal centers, where EBV gene expression is down-modulated, presumably to limit immune-detection. EBV and LMP1 are increasingly detected in diffuse-large B-cell lymphomas of the elderly [13]. While latent EBV infection is detectable in roughly 10% of gastric carcinomas worldwide, only a subset appear to express LMP1 [22]. LMP1 induces cell survival and growth through ligand-independent activation of multiple cell pathways. These include nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), interferon-regulatory factor 7 (IRF7), and phosphatidylinositol 3-kinase (PI3K) pathways [27,28,29]. RF7 pathwaay a activation, w special attention too recent advvances in thee field
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