9.B.387. The Viral Latent Membrane Protein (VLMP) Family
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 (Bentz et al. 2011).
LMP1 of Epstein-Barr virus (EBV) acts as a CD40 functional homolog to prevent apoptosis of infected B-lymphocytes and drive their proliferation. It functions as a constitutively active tumor necrosis factor receptor that induces the activation of several signaling pathways, including those of the NF-kappa-B family. LMP1 signaling leads to up-regulation of antiapoptotic proteins and provide growth signals in latently infected cells. It interacts with host UBE2I and subsequently affects the sumoylation state of several cellular proteins. For example, it induces the sumoylation of host IRF7, thereby limiting its transcriptional activity and modulating the activation of innate immune responses (Bentz et al. 2012). The LMP of Epstein Barr virus LMP1 C-terminal-activating region 3 contributes to LMP1-mediated cellular migration via its interaction With Ubc9 (Bentz et al. 2011).
LMP2A is an EBV-encoded protein with three domains: (a) an N-terminal cytoplasmic domain, which has PY motifs that bind to WW domain-containing E3 ubiquitin ligases and an ITAM that binds to SH2 domain-containing proteins, (b) a transmembrane domain with 12 transmembrane segments that localizes LMP2A in cellular membranes, and (c) a 27-amino acid C-terminal domain which mediates homodimerization and heterodimerization of LMP2 protein isoforms (Cen and Longnecker 2015). The most prominent two isoforms of the protein are LMP2A and LMP2B. The LMP2B isoform lacks the 19-amino acid N-terminal domain found in LMP2A, which modulates cellular signaling resulting in a baseline activation of B cells and degradation of cellular kinases leading to the downregulation of normal B cell signaling pathways. These two seemingly contradictory processes allow EBV to establish and maintain latency. LMP2 is expressed in many EBV-associated malignancies. While its antigenic properties may be useful in developing LMP2-specific immunity, the LMP2A N-terminal motifs also provide a basis to target LMP2A-modulated cellular kinases for the development of treatment strategies (Cen and Longnecker 2015).