title: Hepatitis B virus stimulates G6PD expression through HBx-mediated Nrf2 activation.
abstract: Metabolic reprogramming is a hallmark of physiological changes in cancer. Cancer cells primarily apply glycolysis for cell metabolism, which enables the cells to use glycolytic intermediates for macromolecular biosynthesis in order to meet the needs of cell proliferation. Here, we show that glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the pentose phosphate pathway, is highly expressed in chronic hepatitis B virus (HBV)-infected human liver and HBV-associated liver cancer, together with an elevated activity of the transcription factor Nrf2. In hepatocytes, HBV stimulates by its X protein (HBx) the expression of G6PD in an Nrf2 activation-dependent pathway. HBx associates with the UBA and PB1 domains of the adaptor protein p62 and augments the interaction between p62 and the Nrf2 repressor Keap1 to form HBx-p62-Keap1 complex in the cytoplasm. The aggregation of HBx-p62-Keap1 complexes hijacks Keap1 from Nrf2 leading to the activation of Nrf2 and consequently G6PD transcription. Our data suggest that HBV upregulates G6PD expression by HBx-mediated activation of Nrf2. This implies a potential effect of HBV on the reprogramming of the glucose metabolism in hepatocytes, which may be of importance in the development of HBV-associated hepatocarcinoma.
authors.affiliation: Department of Biochemistry and Molecular Biology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: B
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: M
authors.initials: M
authors.lastname: Fang
authors.affiliation: Department of Biochemistry and Molecular Biology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Z
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Biochemistry and Molecular Biology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: D
authors.initials: D
authors.lastname: Cui
authors.affiliation: Department of Biochemistry and Molecular Biology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: S
authors.initials: S
authors.lastname: Jia
authors.affiliation: Department of Biochemistry and Molecular Biology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: X
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China.
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China.
authors.forename: T
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry and Molecular Biology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China.
authors.forename: W
authors.initials: W
authors.lastname: Liu
mesh_terms: D045744:Cell Line, Tumor; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000378:metabolism*; D019694:Hepatitis B, Chronic / Q000201:enzymology / Q000378:metabolism / Q000821:virology; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000821:virology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D005954:Glucosephosphate Dehydrogenase