Hepatitis C virus/human interactome identifies SMURF2 and the viral protease as critical elements for the control of TGF-β signaling

TGF-β signaling induces epithelial to mesenchymal transition (EMT) and plays an important role in hepatocellular carcinoma (HCC) development. Clinical observations indicate that hepatitis C virus (HCV) chronic infection, which is a major cause of HCC, induces TGF-β signaling perturbations. Here, we investigate the mechanisms by which HCV nonstructural proteins interfere with TGF-β signaling, in human hepatoma cell lines expressing HCV subgenomic replicon. A transcriptomic study showed that TGF-β stimulation of these cells resulted in a protumoral gene expression profile and in up-regulation of EMT-related genes compared to control interferon-treated cells not expressing HCV proteins. We found that the viral protease NS3-4A interacted with SMURF2, a negative regulator of TGF-β signaling. In cells expressing HCV subgenomic replicon or NS3-4A, TGF-β stimulation induced an increased expression of SMAD-dependent genes compared to control cells. This enhanced signaling was suppressed by SMURF2 overexpression an...