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 eIF2alpha 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.
Chan
Shiu-Wan
SW
Faculty of Life Sciences, University of Manchester, 1.800 Stopford Building, Manchester, UK. shiu-wan.chan@manchester.ac.uk
Egan
Philip Anthony
PA
D015153:Blotting, Western; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology; D050684:E2F Transcription Factors / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D015852:Eukaryotic Initiation Factor-2 / Q000502:physiology; D006367:HeLa Cells; D016174:Hepacivirus / Q000502:physiology*; D054884:Host-Pathogen Interactions / Q000502:physiology; D006801:Humans; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology; D056811:Unfolded Protein Response / Q000502:physiology*; D014759:Viral Envelope Proteins / Q000502:physiology*
D050684:E2F Transcription Factors; D015852:Eukaryotic Initiation Factor-2; D016160:Retinoblastoma Protein; D014759:Viral Envelope Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human