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A molecular chaperone glucose‐regulated protein 94 blocks apoptosis induced by virus infection

The hepatitis C virus (HCV) E2 protein has been shown to block apoptosis and has been suggested to facilitate persistent infection of the virus. Here, we report that the anti‐apoptotic activity of E2 is mediated by activation of nuclear factor kappa B (NF‐κB) that directs expression of survival gene products such as tumor necrosis factor (TNF‐α) receptor‐associated factor 2 (TRAF2), X‐chromosome–linked inhibitor of apoptosis protein (XIAP), FLICE‐like inhibitory protein (FLIP), and survivin. Increased levels of these proteins were observed in HCV‐infected cells and a cell line producing HCV E2 protein. The activation of NF‐κB was mediated by HCV‐E2–induced expression of the molecular chaperone glucose‐regulated protein 94 (GRP94). Overexpression of GRP94 alone resulted in expression of anti‐apoptotic proteins and blocked apoptosis induced by tumor‐necrosis–related apoptosis‐inducing ligand (TRAIL). Interestingly, increased levels of GRP94 were observed in cells supporting HCV proliferation that originated from liver tissues from HCV patients. Moreover, small interfering RNA (siRNA) knock‐down of GRP94 nullified the anti‐apoptotic activity of HCV E2. Conclusion: These data indicate that HCV E2 blocks apoptosis induced by HCV infection and the host immune system through overproduction of GRP94, and that HCV E2 plays an important role in persistent HCV infection. (HEPATOLOGY 2008.)