Ns4B Protein Of Hepatitis C Virus Activates Bcl-2and MMP-2Expression Through Multiple Cellular Signaling Pathways

Hepatitis C Virus (HCV) is an RNA virus with envelope belonging to the family Flaviviridae. It contains a positive-sense single-stranded RNA genome which is9600nucleotides in length. There are more than170million people currently affected by chronic HCV infection, it is a major cause of chronic liver diseases worldwide, and it often leads to hepatocellular carcinoma.In this study, we demonstrated that signal transducer and activators of transcription3(STAT3), matrix metalloproteinase-2(MMP-2), and B cell lymphoma2(Bcl-2) were significantly stimulated in HCV-infected patients. We further showed that HCV activates STAT3, MMP2, Bcl-2, extracellular regulated protein kinase (ERK), and c-Jun N-terminal kinase (JNK) in infected Huh7.5.1cells. Functional screening of HCV proteins revealed that the nonstructural protein4B (NS4B) is reponsible for the activation of MMP-2and Bcl-2by stimulating STAT3through repressing the suppressor of cytokine signaling3(SOCS3). Our results also demonstrated 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-2and Bcl-2mediated 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 showed that amino acids227to250of NS4B are essential for regulation of STAT3, JNK, ERK, MMP-2, and Bcl-2, and among them, three residues (237L,239S, and245L) are crucial for this regulation.Thus, we revealed a novel mechanism underlying HCV pathogenesis in which multiple intracellular signal cascades are cooperatively involved in the activation of two important cellular factors, MMP-2, and Bcl-2, in response to HCV infection.