Reactivation of the Epstein-Barr virus from viral latency by an S-adenosylhomocysteine hydrolase/14-3-3 zeta/PLA2-dependent pathway.
The S-adenosylhomocysteine hydrolase (SAH) and 14-3-3 zeta/phospholipase A2 (PLA2) are transcriptionally activated in parallel to the induction of the Epstein-Barr virus (EBV) lytic cycle by the ganglioside IV(3)NeuAc-nLcOse(4)Cer. For analysis of the initiation of the viral reactivation, SAH and 14-3-3 zeta/PLA2 were overexpressed. Expression of EA-D, BZLF1, and BHRF1 was increased in response to both, SAH- and 14-3-3 zeta/PLA2 overexpression indicating the initiation of the EBV lytic cycle. Expression of 14-3-3 zeta/PLA2 was shown to be increased in SAH overexpressing cells. Additionally, SAH-triggered initiation of viral reactivation could be inhibited by PLA2-specific inhibitors. The phosphorylation status of protein kinase C (PKC) was shown to be increased in SAH-overexpressing cells. PKC-specific inhibitors arrested SAH-triggered initiation of viral reactivation. Surprisingly, 14-3-3 zeta/PLA2-induced initiation of viral reactivation did not correlate with PKC activation. PKC-specific inhibitors were of no influence. SAH initiated EBV reactivation via the BZLF1-Zp and the BZLF1-Rp promoter, whereas 14-3-3 zeta/PLA2 was connected to the promoter Rp only. Our results suggest two routes of viral reactivation involving SAH, one associated with PKC and BZLF1-Zp, the other associated with 14-3-3 zeta/PLA2 and BZLF1-Rp.
Maas
Diana
D
Division of Virology, Department of Medical Microbiology, UK Aachen, RWTH Aachen 52057, Aachen, Germany.
Maret
Claudine
C
Schaade
Lars
L
Scheithauer
Simone
S
Ritter
Klaus
K
Kleines
Michael
M
D048948:14-3-3 Proteins / Q000378:metabolism*; D043383:Adenosylhomocysteinase / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral; D054513:Group IV Phospholipases A2; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism / Q000494:pharmacology; D014764:Viral Proteins / Q000378:metabolism / Q000494:pharmacology; D017735:Virus Latency / Q000502:physiology*
D048948:14-3-3 Proteins; C063676:BZLF1 protein, Herpesvirus 4, Human; D004268:DNA-Binding Proteins; D015534:Trans-Activators; D014764:Viral Proteins; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D054467:Phospholipases A2; D043383:Adenosylhomocysteinase