Hepatitis C virus envelope proteins regulate CHOP via induction of the unfolded protein response

Abstract

Unfolded protein response (UPR) is a cellular adaptive response that functions to reduce stress caused by malfolded proteins in the endoplasmic reticulum (ER). UPR can be induced under physiological or pathological conditions and is responsible for the pathogenesis of many human diseases. Hepatitis C virus (HCV) is a single-stranded, positive-sense RNA virus causing chronic diseases. Its genome encodes two envelope proteins E1 and E2, which mature in the ER to form a noncovalently bound, native complex and disulfide aggregates and have previously been shown to induce expression of the molecular chaperone immunoglobulin heavy chain binding protein. In this study, we show that HCV envelope protein expression regulates another stress indicator CCAAT/enhancer-binding protein-homologous protein (CHOP). The ER-stress element and the activating transcription factor 4 element in the CHOP promoter were activated to a similar extent by HCV envelope protein expression. Using mouse embryonic fibroblasts deficient in the ER stress kinase RNA-activated protein kinase-like ER-resident kinase (PERK), we showed that PERK was necessary and sufficient for activating the CHOP promoter. Expression of HCV E1 and/or E2 also induced splicing of X-box binding protein 1 and transactivation of the unfolded protein response element, leading to the speculation that HCV E1 and E2 not only regulate the UPR but also ER-associated degradation.