The hepatitis B virus encoded oncoprotein pX amplifies TGF-beta family signaling through direct interaction with Smad4: potential mechanism of hepatitis B virus-induced liver fibrosis

Hepatitis B, one of the most common infectious diseases in the world, is cl osely associated with acute and chronic hepatitis, cirrhosis, and hepatocel lular carcinoma. Many clinical investigations have revealed that hepatic fi brosis is an important component of these liver diseases caused by chronic hepatitis B. TGF-beta signaling plays an important role in the pathogenesis of fibrosis in chronic hepatitis and cirrhosis. As these diseases are asso ciated with hepatitis B virus (HBV) infection, we examined the possibility that the HBV-encoded pX oncoprotein regulates TGF-beta signaling. We show t hat pX enhances transcriptional activity in response to TGF-beta, BMP-2, an d activin by stabilizing the complex of Smad4 with components of the basic transcriptional machinery. Additionally, confocal microscopic studies sugge st that pX facilitates and potentiates the nuclear translocation of Smads, further enhancing TGF-beta signaling. Our studies suggest a new paradigm fo r amplification of Smad-mediated signaling by an oncoprotein and suggest th at enhanced Smad-mediated signaling may contribute to HBV-associated liver fibrosis.