Activation of the grp78 and grp94 promoters by hepatitis C virus E2 envelope protein

The hepatitis C virus E1 and E2 envelope proteins are targeted to the endop lasmic reticulum, but instead of being secreted, they are retained in a pre -Golgi compartment, at least partly in a misfolded state. Since secretory p roteins which are retained in the endoplasmic reticulum frequently can acti vate the transcription of intraluminal chaperone proteins, we measured the effect of the E1 and E2 proteins on the promoters of two such chaperones, G RP78 (BiP) and GRP94. We found that E2 but not E1 protein activates these t wo promoters, as assayed by a reporter gene system. Furthermore, E2 but not E1 protein induces the synthesis of GRP78 from the endogenous cellular gen e. We also found that E2 but not E1 protein expressed in mammalian cells is bound tightly to GRP78. This association may explain the ability of E2 pro tein to activate transcription, since GRP78 has been postulated to be a sen sor of stress in the endoplasmic reticulum. Since overexpression of GRP78 h as been shown to decrease the sensitivity of cells to killing by cytotoxic T lymphocytes and to increase tumorigenicity and resistance to antitumor dr ugs, this activity of E2 protein may be involved in the pathogenesis of hep atitis C virus-induced diseases.