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Identification of the IFITM3 gene as an inhibitor of hepatitis C viral translation in a stable STAT1 cell line

Summary.  To investigate the functions of signal transducers and activators of transcription 1 (STAT1)‐induced anti‐hepatitis C viral (HCV) effects, a stable Huh7.5 cell line (Huh7.5‐STAT1ER) was established that constitutively expresses a fusion protein (STAT1ER) of STAT1 and the mouse oestrogen receptor (ER), which forms STAT1ER homodimers after 4‐hydroxytamoxifen (4‐HT) treatment. This inducible and cytokine/receptor‐independent STAT1 activation system allowed us to investigate the anti‐HCV effects of STAT1ER activation after inducing IFN‐stimulated gene (ISG) expression. The anti‐HCV effects of dimerized STAT1ER fusion protein were determined by real‐time PCR in a time‐dependent fashion post‐HCV (JFH‐1) infection. HCV (JFH‐1) RNA decreased 48% at 72 h after 4‐HT treatment. To distinguish the inhibitory effects of STAT1ER activation on HCV RNA replication or HCV internal ribosomal entry site (IRES)–mediated translation, a dicistronic pRL‐HL construct was used in the studies. Both cellular (Cap‐dependent) and HCV IRES–mediated (Cap‐independent) translation were decreased by 63% and 57% at 72 h post‐STAT1ER activation in the STAT1ER cell line. In our previous studies, interferon‐induced transmembrane protein 3 [(IFITM3) (1‐8U)] was found to inhibit HCV RNA replication. Subsequently, elevated expression of the 1‐8U gene was confirmed by Western blotting in the Huh7.5‐STAT1ER cell line. To further investigate the 1‐8U function with both in vivo and in vitro studies, the 1‐8U gene was found to suppress cellular and HCV IRES–mediated translation.