An integral membrane protein (LMP2) blocks reactivation of Epstein-Barr virus from latency following surface immunoglobulin crosslinking.
The role of latent membrane protein 2 (LMP2) in Epstein-Barr virus (EBV) infection was evaluated by using latently infected primary B lymphocytes that had been growth transformed by wild-type or specifically mutated EBV recombinants. LMP2 null mutant recombinant EBV-infected cells were similar to normal B lymphocytes in their rapid increase in intracellular free calcium after surface immunoglobulin crosslinking. These cells also became more permissive for lytic EBV replication. In sharp contrast, wild-type control infected cells had little or no increase in intracellular free calcium or in permissivity for EBV replication. The block to surface immunoglobulin crosslinking-induced permissivity in cells expressing wild-type LMP2 could be bypassed by raising intracellular free calcium levels with an ionophore and by activating protein kinase C with phorbol 12-myristate 13-acetate. LMP2A, not LMP2B, mediates this effect on calcium mobilization. Genetic and biochemical data are consistent with these effects being due to the interaction of the LMP2A N-terminal cytoplasmic domain with B lymphocyte src family tyrosine kinases.
Miller
C L
CL
Department of Medicine, Harvard Medical School, Boston, MA 02115.
Lee
J H
JH
Kieff
E
E
Longnecker
R
R
D000595:Amino Acid Sequence; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002213:Capsid / Q000276:immunology; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D003432:Cross-Linking Reagents; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D011493:Protein Kinase C / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology*; D014775:Virus Activation / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects
D000956:Antigens, Viral; D003432:Cross-Linking Reagents; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D011947:Receptors, Antigen, B-Cell; D014763:Viral Matrix Proteins; D000001:Calcimycin; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium