title: Hepatitis C virus activates Bcl-2 and MMP-2 expression through multiple cellular signaling pathways.
abstract: Hepatitis C virus (HCV) infection is associated with numerous liver diseases and causes serious global health problems, but the mechanisms underlying the pathogenesis of HCV infections remain largely unknown. In this study, we demonstrate that signal transducer and activator of transcription 3 (STAT3), matrix metalloproteinase-2 (MMP-2), and B-cell lymphoma 2 (Bcl-2) are significantly stimulated in HCV-infected patients. We further show that HCV activates STAT3, MMP-2, Bcl-2, extracellular regulated protein kinase (ERK), and c-Jun N-terminal kinase (JNK) in infected Huh7.5.1 cells. Functional screening of HCV proteins revealed that nonstructural protein 4B (NS4B) is responsible for the activation of MMP-2 and Bcl-2 by stimulating STAT3 through repression of the suppressor of cytokine signaling 3 (SOCS3). Our results also demonstrate that multiple signaling cascades, including several members of the protein kinase C (PKC) family, JNK, ERK, and STAT3, play critical roles in the activation of MMP-2 and Bcl-2 mediated by NS4B. Further studies revealed that the C-terminal domain (CTD) of NS4B is sufficient for the activation of STAT3, JNK, ERK, MMP-2, and Bcl-2. We also show that amino acids 227 to 250 of NS4B are essential for regulation of STAT3, JNK, ERK, MMP-2, and Bcl-2, and among them, three residues (237L, 239S, and 245L) are crucial for this regulation. Thus, we reveal a novel mechanism underlying HCV pathogenesis in which multiple intracellular signaling cascades are cooperatively involved in the activation of two important cellular factors, MMP-2 and Bcl-2, in response to HCV infection.
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, and Chinese-French Liver Disease Research Institute at Zhongnan Hospital, Wuhan University, Wuhan, China.
authors.forename: Youxing
authors.initials: Y
authors.lastname: Li
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Luo
authors.forename: Lei
authors.initials: L
authors.lastname: Kang
authors.forename: Jing
authors.initials: J
authors.lastname: Qu
authors.forename: Weiyong
authors.initials: W
authors.lastname: Liu
authors.forename: Xueshan
authors.initials: X
authors.lastname: Xia
authors.forename: Yingle
authors.initials: Y
authors.lastname: Liu
authors.forename: Kailang
authors.initials: K
authors.lastname: Wu
authors.forename: Jianguo
authors.initials: J
authors.lastname: Wu
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D002681:China; D017931:DNA Primers / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008156:Luciferases; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D010957:Plasmids / Q000235:genetics; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D018709:Statistics, Nonparametric; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000378:metabolism
chemical_list: D017931:DNA Primers; D019253:Proto-Oncogene Proteins c-bcl-2; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D017361:Viral Nonstructural Proteins; D008156:Luciferases; D020778:Matrix Metalloproteinase 2