Dengue virus subgenomic RNA induces apoptosis through the Bcl-2-mediated PI3k/Akt signaling pathway

We report a RNA species of 429 nucleotides derived from the 3' untranslated region of the viral genome in Dengue 2 virus (DENV-2) infected cells. The 3' terminal of viral RNA contained specific conserved structures that are important for the production of subgenomic RNA. Transient replicon assays suggested that loss of this small RNA has little effect on viral replication, and genetic analysis using recombinant viruses demonstrated that the existence of this subgenomic RNA is not essential for the life cycle of the DENV-2. Results from cytotoxicity and apoptosis assay revealed that the generation of subgenomic RNA is significant for DENV-2 viral cytopathicity and virus-induced apoptosis; and the deficiency could be partially restored by providing subgenomic RNA in trans from transfection. In addition, we found that subgenomic RNA modulates the phosphatidylinositol 3-kinase (PI3k)/Akt signaling pathway through a Bcl-2-related mechanism, resulting in apoptotic cell death.