Effects of hepatitis C virus envelope glycoprotein unfolded protein response activation on translation and transcription

The hepatitis C virus (HCV) envelope glycoproteins have been shown to cause ER stress and induce the unfolded protein response (UPR). Using a bicistronic reporter, we show that the envelope glycoproteins repressed both cap-dependent and HCV IRES-mediated translation in HeLa cells but displayed a differential repression of cap-dependent translation in Huh-7 cells. In contrast, the envelope glycoproteins repressed E2F transcriptional activity in both HeLa and Huh-7 cells and caused increased accumulation of the underphosphorylated retinoblastoma protein. Expression of the envelope glycoproteins induced eIF2 alpha phosphorylation, suggesting a role of the UPR in regulating translation and E2F transcriptional activity. The envelope glycoproteins also enhanced transcriptional activity from the COX-2 promoter and endogenous COX-2 expression in HeLa cells, but not in Huh-7 cells. Together, these results suggest that the envelope glycoproteins may assume more functional roles in viral replication and host cell interactions.