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 host through an ability to establish latent infection with episodic reactivations. In latent infection EBV expresses an integral membrane protein LMP2A that regulates reactivation from latency. LMP2A is constitutively tyrosine phosphorylated and is associated with lyn and syk tyrosine kinases. The activity of lyn is substantially reduced. In EBV-infected cells in which LMP2A is expressed, crosslinking of sIg fails to trigger the protein tyrosine kinase signal cascade, tyrosine phosphorylation of cell proteins does not change, second messengers are not generated, and lytic EBV infection is not induced. In contrast, crosslinking of sIg on cells infected with EBV recombinants with null mutations in LMP2A results in transient tyrosine phosphorylation of lyn, syk, phospholipase C gamma 2 and phosphatidylinositol-3' kinase, transiently increased intracellular free calcium, and reactivation of lytic EBV infection. These studies describe a novel molecular regulator of herpesvirus latency and focus attention on the importance of transmembrane signal transduction in herpes virus reactivation from latency. They support the working hypothesis that the identification of ligand-receptor interactions that can result in the induction of reactivation will provide an important inroad toward the delineation of the molecular mechanism, which govern herpesvirus reactivation from latency.
Miller
C L
CL
Department of Microbiology, Harvard University, Boston, Massachusetts 02115.
Lee
J H
JH
Kieff
E
E
Burkhardt
A L
AL
Bolen
J B
JB
Longnecker
R
R
D000595:Amino Acid Sequence; D000818:Animals; D000956:Antigens, Viral / Q000502:physiology*; D002472:Cell Transformation, Viral; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D007071:Immunoglobulin A, Secretory / Q000378:metabolism*; D008969:Molecular Sequence Data; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014763:Viral Matrix Proteins / Q000502:physiology*; D014775:Virus Activation / Q000502:physiology*
D000956:Antigens, Viral; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D007071:Immunoglobulin A, Secretory; D014763:Viral Matrix Proteins; D011505:Protein-Tyrosine Kinases