title: Hepatitis B virus X protein binding to hepsin promotes C3 production by inducing IL-6 secretion from hepatocytes.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Gene Research Center, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Gene Research Center, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Biochemistry and Molecular Biology, Gene Research Center, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Chunyi
authors.initials: C
authors.lastname: Zhang
mesh_terms: D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D016022:Case-Control Studies; D002478:Cells, Cultured; D003176:Complement C3 / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D006509:Hepatitis B / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology; D006515:Hepatitis B virus / Q000502:physiology; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: C038245:C3 protein, human; D003176:Complement C3; C508600:IL6 protein, human; D015850:Interleukin-6; D012333:RNA, Messenger; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D012697:Serine Endopeptidases; C055645:hepsin
keywords: complement C3; hepatitis B virus X protein; hepatocellular carcinoma; hepsin; interleukin-6