Latent Membrane Protein 1 Is a Novel Determinant of Epstein-Barr Virus Genome Persistence and Reactivation

Abstract

Latent membrane protein 1 (LMP1) is a constitutively active oncogenic signaling protein encoded by Epstein-Barr virus (EBV). Despite monoclonal infection in cases of nasopharyngeal carcinoma (NPC), it has been difficult to reconcile the heterogeneous LMP1 protein levels detected in tumor cells. The LMP1 protein is a pleiotropic signaling protein with oncogenic potential. Findings from this study are consistent with the hypothesis that LMP1 has a role distinct from that of oncogenesis that facilitates the viral life cycle by promoting an unstable but productive infection in differentiating epithelia.

Exosomal cyclophilin A as a novel noninvasive biomarker for Epstein‐Barr virus associated nasopharyngeal carcinoma

“…Epstein‐Barr virus (EBV) is a ubiquitous human herpesvirus, and establishes lifelong latent infection with more than 90% seropositively in adults . So far, quantitative assessment of circulating EBV DNA has been recognized in clinics for population screening, disease surveillance, and prognostication as a potent biomarker in NPC .…”

“…The EBV latent membrane protein 1 (LMP1) is a latent oncogenic protein encoded by EBV. Studies show that LMP1 harbors the oncogenic potential through NF‐κB signaling pathway and contributes to the viral life cycle in differentiating epithelia …”

New Insights from Elucidating the Role of LMP1 in Nasopharyngeal Carcinoma

“…Apart for HEK293 cells that produce high titer infectious virus, conventional chemical induction methods by 12- O -tetradecanoylphorbol 13-acetate (TPA) and sodium butyrate treatment (or other histone deacetylase [HDAC] inhibitors such as SAHA), or by transfection of the EBV immediate-early switch protein “Z” and the late glycoprotein “gB”, do not always result in efficient production of progeny virus that spread despite induction of lytic genes [ 9 , 30 , 59 ]. Cell lines (primary or immortalized) can be subjected to a variety of molecular virology techniques including immunoblotting, RNA-seq, Southern blotting to differentiate latent fused episomal genomes from linear replicating genomes, titering by quantitative polymerase chain reaction (qPCR) of encapsidated DNase-resistant EBV genomes, and scoring for infectious units by the green Raji assay [ 26 , 60 ]. Immunostaining methods that afford single cell resolution are also crucial when studying diversified cell types representative of polarized primary epithelial tissue, or when assessing differences in infection outcome from the basolateral and apical surfaces [ 23 ].…”

“…The ALI culture method that preserves the diversity of cell types in primary airway epithelial cells may help to answer new questions regarding the expression and distribution (basolateral or apical) of Ephrin A2 in different donors, and potentially identify differences in EBV-infection susceptibility and outcome. While there is no clear explanation for the lack of LMP1 detection in pre-neoplastic nasopharyngeal tissue but consistent detection in preinvasive lesions (dysplastic and carcinoma in situ), culture systems that retain the diversity of cell types representative of primary tissue may help to stratify the expression of LMP1 in different cell types upon de novo infection and possibly during the early events of oncogenesis [ 22 , 26 , 27 , 66 , 67 ].…”

“…Therefore, several important questions remain in elucidating how EBV maintains latency and the origin of clonal EBV genomes in the NPC tumor [ 7 , 24 , 25 ]. Despite knowledge of LMP1 oncogenic signaling properties, the biological function of LMP1 in EBV pathogenesis has yet to be fully elucidated [ 15 , 17 , 26 , 27 ].…”