HBV Protein X Potentiates TGF Beta Signaling

Science's STKE  06 Mar 2001:
Vol. 2001, Issue 72, pp. tw1
DOI: 10.1126/stke.2001.72.tw1

Hepatitis B virus (HBV) infection leads to several potentially life-threatening hepatic diseases. Similarly, dysregulated, chronic TGF-β signaling can also result in liver damage by extracellular matrix proteins whose accumulation has been implicated in several liver diseases. Lee et al. have uncovered a link between HBV infection and the potentiation of TGF-β signaling. The HBV protein X (pX) is required for HBV replication and stimulates transcription through viral and cellular promoters. Transfectin of pX into cells treated with TGF-β, activin, or bone morphogenetic protein-2 (BMP-2), resulted in greatly increased Smad-dependent transcription, in vitro and in vivo. pX associated with Smad4 constitutively, and with Smad3 in a TGF-β-dependent manner, and expression of pX resulted in great increases of Smad3 and Smad4 transport into the nucleus. pX also associated with TFIIB, a component of the basal transcription complex, and stabilized the interaction of Smad3 and Smad4 with TFIIB. pX also relieved the E1A-dependent interference of Smad3-p300 interactions which resulted in increased transcription. Thus, because TGF-β has an established role in chronic hepatitis and cirrhosis, these data suggest that pX potentiates TGF-β-directed pathogenesis and may explain how HBV causes such delibitating liver diseases. These studies also reveal pX as a possible target for drug therapy to lessen disease symptoms caused by HBV.

D. K. Lee, S. H. Park, Y. Yi, S.-G. Choi, C. Lee, W. T. Parks, H. S. Cho, M. P. de Caestecker, Y. Shaul, A. B. Roberts, S.-J. Kim, The hepatitis B virus encoded oncoprotein pX amplifies TGF-β family signaling through direct interaction with Smad4: potential mechanism of hepatitis B virus-induced liver fibrosis. Genes Dev. 15, 455-466 (2001). [Abstract] [Full Text]