The Latent Membrane Protein 1 (LMP1): Biological Functions and Molecular Mechanisms.

Abstract

Nearly two decades after the discovery of Epstein-Barr virus (EBV), the latent membrane protein 1 (LMP1) was identified and recognized as the primary transforming gene product of the virus. LMP1 is expressed in most EBV-associated lymphoproliferative diseases and malignancies, where it plays a central role in pathogenesis. Over 40 years of research have established LMP1 as a potent driver of cellular transformation and survival, deregulating key signaling pathways, cellular metabolism, and transcription while simultaneously subverting programmed cell death mechanisms. Beyond its role in transformation and immortalization, LMP1 exerts multifaceted biological activities supporting tumorigenesis, including immune modulation, regulation of the tumor microenvironment, and promotion of migration and invasive tumor growth. Functioning as a constitutively active receptor that mimics co-stimulatory CD40 receptor signals in B-lymphocytes, LMP1 recruits cellular signaling molecules associated with tumor necrosis factor receptors (TNFRs), such as TNFR-associated factors (TRAFs) and the TNFR-associated death domain protein (TRADD). It triggers phosphorylation, ubiquitination, and SUMOylation events in the target cell to activate NF-κB, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), interferon regulatory factor (IRF), and STAT pathways. This review provides an updated and comprehensive overview of the biological and molecular functions of LMP1, highlighting its role as a critical interface in virus-host interactions and its potential as a therapeutic target.