EPSTEIN-BARR-VIRUS PROTEIN LMP2A REGULATES REACTIVATION FROM LATENCY BY NEGATIVELY REGULATING TYROSINE KINASES INVOLVED IN SIG-MEDIATED SIGNAL-TRANSDUCTION

Like other herpesviruses, Epstein-Barr Virus (EBV) persists in its hos t through an ability to establish latent infection with episodic react ivations. In latent infection EBV expresses an integral membrane prote in LMP2A that regulates reactivation from latency. LMP2A is constituti vely tyrosine phosphorylated and is associated with lyn and syk tyrosi ne kinases. The activity of lyn is substantially reduced. In EBV-infec ted cells in which LMP2A is expressed, crosslinking of sig fails to tr igger the protein tyrosine kinase signal cascade, tyrosine phosphoryla tion of cell proteins does not change, second messengers are not gener ated, and lytic EBV infection is not induced. In contrast, crosslinkin g of sig on cells infected with EBV recombinants with null mutations i n LMP2A results in transient tyrosine phosphorylation of lyn, syk, pho spholipase C gamma 2 and phosphatidylinositol-3' kinase, transiently i ncreased intracellular free calcium, and reactivation of lytic EBV inf ection. These studies describe a novel molecular regulator of herpesvi rus latency and focus attention on the importance of transmembrane sig nal transduction in herpes virus reactivation from latency. They suppo rt the working hypothesis that the identification of ligand-receptor i nteractions that can result in the induction of reactivation will prov ide an important inroad toward the delineation of the molecular mechan ism, which govern herpesvirus reactivation from latency.