Hepatitis B virus X protein binding to hepsin promotes C3 production by inducing IL-6 secretion from hepatocytes
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Mingming Zhang1, Jianxin Gu1, Chunyi Zhang1
1Department of Biochemistry and Molecular Biology, Gene Research Center, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
Chunyi Zhang, e-mail: [email protected]
Keywords: hepatitis B virus X protein, hepsin, complement C3, interleukin-6, hepatocellular carcinoma
Received: August 06, 2015 Accepted: January 01, 2016 Published: January 08, 2016
Hepatitis B virus (HBV) X protein (HBx) is an important effector for HBV-associated pathogenesis. In this study, we identified hepsin as an HBx-interacting protein and investigated the effects of hepsin on HBx-mediated complement component 3 (C3) secretion in hepatocytes. In vivo and in vitro binding between HBx and hepsin was confirmed by co-immunoprecipitation and Glutathione S-transferase pull-down assays. HBx synergized with hepsin to promote C3 production by potentiating interleukin-6 (IL-6) secretion. Knockdown of endogenous hepsin attenuated C3 and IL-6 secretion induced by HBx in hepatic cells. In addition, levels of hepsin protein correlated positively with C3 expression in human non-tumor liver tissues. Further exploration revealed that HBx and hepsin increased C3 promoter activity by up-regulating the expression and phosphorylation of the transcription factor CAAT/enhancer binding protein beta (C/EBP-β), which binds to the IL-6/IL-1 response element in the C3 promoter. HBx and hepsin synergistically enhanced IL-6 mRNA levels and promoter activity by increasing the nuclear translocation of nuclear factor kappaB (NF-κB). Our findings show for the first time that binding between HBx and hepsin promotes C3 production by inducing IL-6 secretion in hepatocytes.
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