Hepatitis C Virus Non-structural Protein 4B Induces Unfolded Protein Response

The unspliced and spliced forms of XBP1 stably expressing NS4B in HeLa cells, the transcriptional levels of ATF6, Grp78 and caspase-12, and the luciferase activity in XBP1 and Grp78 promoter reporter assays in HeLa and Huh-7 cells expressing NS4B were detected. The results showed that the two forms of XBP1 were detected NS4B in HeLa cells, moreover, ATF6 and Grp78 transcription levels and the luciferase activity in XBP1 and Grp78 promoter assays in cells expressing NS4B increased compared with that of cells without NS4B expression due to XBP1 binding to their promoter sites. Collectively, the results imply the possibility that NS4B induces UPR through ATF6 or IRE1-XBP1 pathways upon ER stress, and maybe play some roles in HCV pathogenesis, in particular, in chronic hepatitis, even hepatocellular carcinoma.