Epstein-Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival.
Many cells latently infected with Epstein-Barr virus (EBV), including certain virus-associated tumors, express latent membrane protein 2A (LMP2A), suggesting an important role for this protein in viral latency and oncogenesis. LMP2A mimics B-cell receptor signaling but can also act as a decoy receptor blocking B-cell receptor (BCR) activation. Studies of peripheral B cells have not resolved this apparent contradiction because LMP2A seems to be dispensable for EBV-induced transformation of these B cells in vitro. We show here that LMP2A is essential for growth transformation of germinal center B cells, which do not express the genuine BCR because of deleterious somatic hypermutations in their immunoglobulin genes. BCR-positive (BCR(+)) and BCR-negative (BCR(-)) B cells are readily transformed with a recombinant EBV encoding a conditional, floxed LMP2A allele, but the survival and continued proliferation of both BCR(+) and BCR(-) B cells is strictly dependent on LMP2A. These findings indicate that LMP2A has potent, distinct antiapoptotic and/or transforming characteristics and point to its role as an indispensable BCR mimic in certain B cells from which human B-cell tumors such as Hodgkin lymphoma originate.
GSF-National Research Center for Environment and Health Department of Gene Vectors, Munich, Germany.
Christoph
C
Mancao
Wolfgang
W
Hammerschmidt
D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000502:physiology*; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D006689:Hodgkin Disease / Q000209:etiology / Q000235:genetics; D006801:Humans; D018716:Molecular Mimicry / Q000235:genetics / Q000502:physiology*; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics / Q000502:physiology*; D014763:Viral Matrix Proteins / Q000502:physiology*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr