Oncogenic Activity of Epstein-Barr Virus Latent Membrane Protein 1 (LMP-1) Is Down-Regulated by Lytic LMP-1

Abstract

The Epstein-Barr virus (EBV) is an oncogenic human herpesvirus. EBV latent membrane protein 1 (LMP-1) is a viral oncogene that manifests its oncogenic phenotype through activation of cellular signaling pathways involved in cell growth, survival, differentiation, and transformation. Lytic LMP-1 (lyLMP-1) is a related EBV gene without oncogenic properties. The lyLMP-1 gene is found in 60% of the EBV strains circulating in nature, but it is not found in EBV strains associated with nasopharyngeal carcinoma. We recently demonstrated that lyLMP-1 down-regulates the half-life of LMP-1 in epithelial cells. Therefore in this study, we tested the hypothesis that lyLMP-1 concomitantly down-regulates LMP-1 oncogenic activity. The results demonstrated that lyLMP-1 inhibits LMP-1-mediated intracellular signaling activation, epithelial cell growth and survival, and fibroblast cell transformation in a dose-dependent manner. Lytic LMP-1 manifested this effect through the promotion of LMP-1 degradation and a reduction in the expressed quantity of LMP-1. Thus, lyLMP-1 functions as a posttranslational negative regulator of LMP-1 oncogenesis. These results support a model of EBV-associated epithelial oncogenesis in which lyLMP-1 may act in vivo to reduce the risk of LMP-1-mediated transformation and is therefore subjected to negative selection in nasopharyngeal carcinoma pathogenesis. Epstein-Barr virus (EBV)is an oncogenic human herpesvirus associated with a broad spectrum of benign and malignant diseases, including infectious mononucleosis, oral hairy leukoplakia, African Burkitt's lymphoma, Hodgkin's disease lymphoma, lymphoproliferative disorders of immunocompromised hosts, and nasopharyngeal carcinoma. The EBV latent membrane protein 1 (LMP-1) is a viral oncogene (30) that is believed to be important in the pathogenesis of many EBVassociated diseases, including nasopharyngeal carcinoma (25). In the B958 EBV strain, LMP-1 is a 63-kDa protein of 386 amino acids encoded by the BNLF1 gene. LMP-1 localizes to cellular membranes and functions as a constitutively active tumor necrosis factor receptor homologue that propagates intracellular signaling, including the NF-B, cJun N-terminal protein kinase/AP-1, and Janus kinase/STAT pathways (5,12,15,27). Through these signaling pathways, LMP-1 generates a myriad of effects on host cell growth, differentiation, and apoptosis, including growth promotion and survival in epithelial cells (4,11,16,23,32) and transformation of rodent fibroblasts (3, 30). Although the mechanisms by which LMP-1 influences cell biology have been intensively studied, little is known about the mechanisms that regulate LMP-1 oncogenic activity. Some EBV strains also encode an amino-terminally truncated form of LMP-1 called lytic LMP-1 (lyLMP-1). Transcription of lyLMP-1 is driven by the ED-L1A promoter that is located in the first intron of the LMP-1 gene and that is present in all EBV strains (6, 17, 29) (Fig. 1). However, the presence or absence of the lyLMP-1 open reading frame (ORF) is determined by the sequence ...

(-)-Epigallocatechin‑3‑gallate inhibition of Epstein‑Barr virus spontaneous lytic infection involves downregulation of latent membrane protein 1

“…lyLMP1, has 258 amino acid residues ~42-kD, expressed in the lytic phase (43). Modulation of LMP1-activated signaling pathways was the first identified biological activity associated with lyLMP1, and this activity may contribute to the progression of EBV's lytic cycle (43,44). The present findings also suggested that LMP1 and lyLM1 were expressed in B95-8 and CNE1-LMP1 cells and that there was spontaneous reactivation of EBV in the cell lines.…”

Epstein-Barr Virus Large Tegument Protein BPLF1 Contributes to Innate Immune Evasion through Interference with Toll-Like Receptor Signaling

“…S4). LyLMP1 does not activate NF-κB signaling itself and in fact appears to counteract (latent FL) LMP1 signaling [59], [60]. Whereas during latency LMP1 provides proliferative and survival signals through NF-κB, lyLMP1 could cooperate with BPLF1 to reduce NF-κB activation in B cells producing new virions.…”

Modulation of LMP1 protein expression by EBV-encoded microRNAs

“…Methylation of the LMP1 5Ј regulatory region has been noted in NPCs with undetectable LMP1 expression (22,23). The expression of lytic LMP1 has been proposed as a posttranslational regulatory mechanism (24). However, the promoter that drives the lytic form of LMP1 protein is consistently absent from EBV strains isolated from NPC.…”