title: Hepatitis C virus/human interactome identifies SMURF2 and the viral protease as critical elements for the control of TGF-β signaling.
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.
authors.affiliation: 1Centre International de Recherche en Infectiologie, INSERM U1111, 21 av. Tony Garnier, F-69007 Lyon, France. laure.perrin@inserm.fr.
authors.forename: Amandine
authors.initials: A
authors.lastname: Verga-Gérard
authors.forename: Marine
authors.initials: M
authors.lastname: Porcherot
authors.forename: Laurène
authors.initials: L
authors.lastname: Meyniel-Schicklin
authors.forename: Patrice
authors.initials: P
authors.lastname: André
authors.forename: Vincent
authors.initials: V
authors.lastname: Lotteau
authors.forename: Laure
authors.initials: L
authors.lastname: Perrin-Cocon
mesh_terms: D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000502:physiology; D016174:Hepacivirus / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000502:physiology*
chemical_list: D016212:Transforming Growth Factor beta; D017361:Viral Nonstructural Proteins; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases
keywords: EMT; hepatocellular carcinoma; transforming growth factor-β