title: Hepatitis B virus replication and sex-determining region Y box 4 production are tightly controlled by a novel positive feedback mechanism.
abstract: Hepatitis B virus (HBV) infection is a major cause of liver diseases. However, the mechanisms underlying HBV infection and pathogenesis remain largely unknown. The sex-determining region Y box 4 (Sox4) is a transcriptional factor, which preferentially regulates the development of various organs, tissues, and cancers. But, the role of Sox4 in viral infection and pathogenesis has not been elucidated. Here, we demonstrated that Sox4 is up-regulated by HBV, and revealed the mechanism by which HBV regulates Sox4 expression. First, HBV stimulates Sox4 expression through transcriptional factor Yin Yang 1 (YY1), which binds to Sox4 promoter to activate Sox4 transcriptional activity. Second, miR-335, miR-129-2 and miR-203 inhibit Sox4 expression by targeting its mRNA 3'UTR, while HBV suppresses the microRNAs expression, resulting in up-regulating Sox4 post-transcriptionally. Third, Sox4 protein is degraded by proteasome, while HBV surface protein (HBsAg) prevents Sox4 from degradation by directly interacting with the protein, thereby enhancing Sox4 production post-translationlly. More interestingly, HBV-activated Sox4 in turn facilitates HBV replication by direct binding to the viral genome via its HMG box. Thus, this study revealed a novel positive feedback mechanism by which Sox4 production and HBV replication are tightly correlated.
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Shang
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, P.R. China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, P.R. China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, P.R. China.
authors.forename: Jiayin
authors.initials: J
authors.lastname: Mo
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, P.R. China.
authors.forename: Xueping
authors.initials: X
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, P.R. China.
authors.forename: Yingle
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, P.R. China.
authors.forename: Kailang
authors.initials: K
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, P.R. China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Wu
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000209:etiology; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D016679:Genome, Viral; D006509:Hepatitis B / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000821:virology*; D006515:Hepatitis B virus / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology; D020935:MAP Kinase Signaling System; D035683:MicroRNAs / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055751:SOXC Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication; D050986:YY1 Transcription Factor / Q000378:metabolism
chemical_list: D035683:MicroRNAs; C083431:SOX4 protein, human; D055751:SOXC Transcription Factors; D014764:Viral Proteins; D050986:YY1 Transcription Factor; D046988:Proteasome Endopeptidase Complex