New Insights from Elucidating the Role of LMP1 in Nasopharyngeal Carcinoma

Abstract

Latent membrane protein 1 (LMP1) is an Epstein-Barr virus (EBV) oncogenic protein that has no intrinsic enzymatic activity or sequence homology to cellular or viral proteins. The oncogenic potential of LMP1 has been ascribed to pleiotropic signaling properties initiated through protein-protein interactions in cytosolic membrane compartments, but the effects of LMP1 extend to nuclear and extracellular processes. Although LMP1 is one of the latent genes required for EBV-immortalization of B cells, the biology of LMP1 in the pathogenesis of the epithelial cancer nasopharyngeal carcinoma (NPC) is more complex. NPC is prevalent in specific regions of the world with high incidence in southeast China. The epidemiology and time interval from seroconversion to NPC onset in adults would suggest the involvement of multiple risk factors that complement the establishment of a latent and persistent EBV infection. The contribution of LMP1 to EBV pathogenesis in polarized epithelia has only recently begun to be elucidated. Furthermore, the LMP1 gene has emerged as one of the most divergent sequences in the EBV genome. This review will discuss the significance of recent advances in NPC research from elucidating LMP1 function in epithelial cells and lessons that could be learned from mining LMP1 sequence diversity.

Keywords: Epstein-Barr virus; LMP1; epithelial infection; nasopharyngeal carcinoma.

Figure 1

Confocal images of primary human nasal epithelial air-liquid interface (ALI) culture cryosections immunostained for cellular markers. Images were acquired on a Nikon A1 point scanning confocal microscope, processed with NIS Elements, and Z-stack 3D renderings are projected in the x-y plane.

Figure 2

Maximum-likelihood phylogeny of LMP1 sequences. LMP1 sequences were derived from NPC patients (blue) or spontaneously immortalized lymphoblastoid cell lines (sLCLs) (black), which were further grouped by infectious mononucleosis (green) and post-transplant lymphoproliferative disease (red). One sample was directly sequenced from the saliva of a healthy donor (purple). The evolutionary history was inferred by using the Maximum Likelihood method based on the Tamura-Nei model in MEGA7 [100,101]. The tree is to scale, with branch lengths measured in the number of substitutions per site. The analysis involved 69 informative nucleotide sequences. All positions containing gaps and missing data were eliminated, leaving a total of 991 positions in the final dataset.

Figure 3

Conservation plots of LMP1 amino acid residues translated from annotated EBV genomes derived from NPC tumors (NPC), spontaneous LCLs (sLCL), and sLCLs typed with China1 LMP1 sequence (China1, sLCL) or, China1 and derivative hybrid sequences (China1 + derivatives, sLCL) [37,90,92,93,96,97,98]. Conservation plots were generated in CLC Main Workbench 6 and compared to a consensus sequence. A consensus sequence was generated from the combined sequences of NPC and sLCL samples by majority with no gaps and was included in all conservation plots to constrain the number of amino acids to the same total number in all comparisons.