p48 (ISGF-3γ) Is Involved in Interferon-α-induced Suppression of Hepatitis B Virus Enhancer-1 Activity

Interferon-α (IFN-α) suppresses hepatitis B virus (HBV) gene expression by reducing its enhancer-1 activity. IFN-α induces transcription factors, interferon-stimulated gene factor 3 (ISGF3), and interferon regulatory factor-1 (IRF-1), which activate interferon-inducible gene expression through binding to the interferon-stimulated regulatory element (ISRE) “AGTTTCNNTTTCNC” in the gene promoters. We found the ISRE-like sequence “AGGCTTTCACTTTCTC” in the HBV enhancer-1 region and elucidated the role of this sequence. Gel mobility shift assay showed binding of in vitro translated IRF-1 and in vitro translated p48 (ISGF3-γ), which is a component of ISGF3 to this sequence. However, nuclear extracts binding to this sequence from human hepatoma cells (HuH-7) treated with IFN-α contained only the protein consisted of p48. In transfection experiments, IFN-α suppressed the HBV enhancer-1 activity, and overexpression of p48 enhanced this inhibitory effect. Both mutation and deletion of the ISRE-like sequence in the HBV enhancer-1 region reduced the suppressive effect of IFN-α. Our results suggest that the ISRE-like sequence in the HBV enhancer-1 can interact with the protein containing p48 and mediate the IFN-α-induced suppression of the enhancer activity.