Background: Rta is a transcription factor encoded by Epstein-Barr virus (EBV) that activates the transcription of vial lytic genes and promotes lytic development. Results: RNF4 enhances the ubiquitination of Rta, thus decreasing lytic replication and virions production. Conclusion: RNF4 targets SUMO-2-conjugated Rta and promotes Rta ubiquitination. Significance: RNF4 is a SUMO-targeted ubiquitin ligase of Rta that modulates the amount of Rta during EBV lytic progression.

BACKGROUND AND PURPOSENeuropeptide Y (NPY) is a 36-amino acid polypeptide found abundantly in the central and peripheral nervous systems. NPY exerts a potent depressor effect via the activation of both Y1 and Y2 receptors in the nucleus tractus solitarii (NTS) of rats. However, the precise mechanisms involved in this NPY-mediated action remained unclear. EXPERIMENTAL APPROACHEffects of a selective antagonist of Y1 receptors, a PKC inhibitor, a PI3 kinase inhibitor, a NOS inhibitor, an endothelial NOS (eNOS)-selective inhibitor, a neuronal NOS (nNOS)-specific inhibitor or a MAPK inhibitor, on responses to microinjection of NPY into the NTS of Wistar-Kyoto rats were studied to determine the underlying mechanisms. Blood pressure and heart rate were measured and, in NTS, protein phosphorylation assessed by immunohistochemical techniques. KEY RESULTSUnilateral microinjection of exogenous NPY (4.65 pmol/60 nL) into the NTS of urethane-anesthetized Wistar-Kyoto rats markedly decreased blood pressure and heart rate. Microinjection of the Y1 receptor antagonist BIBP3226 or the Gi/Go-protein inhibitor, Pertussis toxin, into the NTS attenuated these NPY-induced hypotensive effects. A selective Y1 receptor agonist increased expression of ERK1/2, ribosomal protein S6 kinase (RSK) and the phosphorylation of eNOS. RSK also bound directly to eNOS and induced its phosphorylation at Ser 1177 . Pretreatment of the NTS with an eNOS inhibitor, but not a nNOS inhibitor, attenuated the NPY-induced hypotensive effects. CONCLUSIONS AND IMPLICATIONSTogether, these results suggested that NPY-induced depressor effects were mediated by activating NPY Y1 receptor-PKC-ERK-RSK-eNOS and Ca 2+ -eNOS signalling pathways, which are involved in regulation of blood pressure in the NTS.

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