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• W1974093529 endingPage "4040" @default.
• W1974093529 startingPage "4027" @default.
• W1974093529 abstract "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 and mimicked by SMURF2 silencing. In addition, NS3-4A expression resulted in an increased and prolonged TGF-β-induced phosphorylation of SMAD2/3 that was abrogated by SMURF2 overexpression. Neither NS3-4A protease activity nor SMURF2 ubiquitin-ligase activity was required to affect TGF-β signaling. Therefore, by targeting SMURF2, NS3-4A appears to block the negative regulation of TGF-β signaling, increasing the responsiveness of cells to TGF-β. Verga-Gérard, A., Porcherot, M., Meyniel-Schicklin, L., André, P., Lotteau, V, and Perrin-Cocon, L. Hepatitis C virus/human interactome identifies SMURF2 and the viral protease as critical elements for the control of TGF-β signaling. FASEB J. 27, 4027–4040 (2013). www.fasebj.org" @default.
• W1974093529 created "2016-06-24" @default.
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• W1974093529 date "2013-06-18" @default.
• W1974093529 modified "2023-09-27" @default.
• W1974093529 title "Hepatitis C virus/human interactome identifies SMURF2 and the viral protease as critical elements for the control of TGF‐β signaling" @default.
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• W1974093529 doi "https://doi.org/10.1096/fj.13-229187" @default.
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