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Hepatitis C virus/human interactome identifies SMURF2 and the viral protease as critical elements for the control of TGF‐β signaling
Author(s) -
VergaGérard Amandine,
Porcherot Marine,
MeynielSchicklin Laurène,
André Patrice,
Lotteau Vincent,
PerrinCocon Laure
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-229187
Subject(s) - signal transduction , biology , hepatitis c virus , gene silencing , ns3 , cancer research , microbiology and biotechnology , virology , virus , gene , biochemistry
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