The role of hepatitis B virus X protein is related to its differential intracellular localization

Ma, Jingwei; Sun, Tucheng; Park, Su‐Jin; Shen, Guanxin; Liu, Junwei

doi:10.1093/abbs/gmr048

Cited by 34 publications

(25 citation statements)

References 56 publications

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“…However, high levels of HBx expression lead to abnormal distribution of mitochondria. The dynamic distribution of HBx may be important to the multiple functions of HBx at different stages of the HBV life cycle (Henkler et al, 2001;Ma et al, 2011). We found that cytoplasmic HBx (HBx-NES) could induce ROS and c-H2AX foci formation, whereas nuclear HBx (HBx-NLS) could not.…”

Section: Discussionmentioning

confidence: 89%

“…4a, right). HBx localizes in the nucleus, cytoplasm or mitochondria depending on its expression level, and its subcellular localization is important for its pleotropic effects at various stages of carcinogenesis (Henkler et al, 2001;Ma et al, 2011). Therefore, we employed two retargeting mutants of HBx, pHBx-NLS and pHBx-NES, which, respectively, encode HBx containing a nuclear localization signal (NLS) or a nuclear export signal (NES) at the N terminus.…”

Section: Hbx Increases Cellular Ros Levels Which Correlate With Actimentioning

confidence: 99%

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Hepatitis B virus X protein activates the ATM–Chk2 pathway and delays cell cycle progression

Kim

Lee

et al. 2015

Journal of General Virology

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Genetic instability is intimately associated with tumour development. In particular, liver cancers associated with hepatitis B virus (HBV) exhibit high genetic instability; however, our understanding of the underlying molecular mechanisms remains limited. In this study, we found that c-H2AX, a marker of DNA double-strand breaks (DSBs), and the levels of phospho-Chk2 (p-Chk2, the activated form) were significantly elevated in HBV-associated hepatocellular carcinomas and neighbouring regenerating nodules. Likewise, introduction of the pHBV or pMyc-HBx plasmids into cells induced accumulation of c-H2AX foci and increased the p-Chk2 level. In these cells, inhibitory phosphorylation of Cdc25C phosphatase (Ser 216 ) and CDK1(Tyr 15 ) was elevated; consequently, cell-cycle progression was delayed at G 2 /M phase, suggesting that activation of the ATM-Chk2 pathway by the HBV X protein (HBx) induces cell-cycle delay. Accordingly, inhibition of ataxia telangiectasia mutated (ATM) by caffeine or siRNA abolished the increase in the p-Chk2 level and restored the delayed CDK1 kinase activity in ChangX cells. We also found that cytoplasmic HBx, but not nuclear HBx, induced reactive oxygen species (ROS) production and led to the accumulation of c-H2AX foci and the increased p-Chk2 level. Together, these data indicate that HBx-induced ROS accumulation induces DNA damage that activates the ATM-Chk2 pathway. Our findings provide insight into the mechanisms of HBV pathogenesis.

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Section: Discussionmentioning

confidence: 89%

Section: Hbx Increases Cellular Ros Levels Which Correlate With Actimentioning

confidence: 99%

Hepatitis B virus X protein activates the ATM–Chk2 pathway and delays cell cycle progression

Kim

Lee

et al. 2015

Journal of General Virology

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“…The specific function of HBx is linked to its subcellular localization (4). It is generally believed that HBx is mostly cytoplasmic, with a small fraction in the nucleus and many groups have reported that the mitochondrion is a major target for HBx in the cytoplasm (5,6), causing mitochondrial damage by regulating mitochondrial membrane potential (7), increasing the generation of cellular reactive oxygen species (ROS) (8,9) and modulating the opening of the mitochondrial permeability transition pore (MPTP).…”

Section: Introductionmentioning

confidence: 99%

Hepatitis B virus X protein sensitizes HL-7702 cells to oxidative stress-induced apoptosis through modulation of the mitochondrial permeability transition pore

Gao

Cai

et al. 2016

Oncology Reports

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Chronic hepatitis B virus (HBV) infection is a leading cause of liver cirrhosis and cancer. Among the pathogenic factors of HBV, HBV X protein (HBx) is attracting increased attention. Although it is documented that HBx is a multifunctional regulator that modulates cell inflammation and apoptosis, the exact mechanism remains controversial. In the present study, we explored the effect of HBx on oxidative stress-induced apoptosis in normal liver cell line, HL-7702. Our results showed that the existence of HBx affected mitochondrial biogenesis by modulating the opening of the mitochondrial permeability transition pore (MPTP). Notably, this phenomenon was associated with a pronounced translocation of Bax from the cytosol to the mitochondria during the period of exposure to oxidative stress with a release of cytochrome c and activation of cleaved caspase-3 and PARP. Moreover, MPTP blockage with cyclosporin A prevented the translocation of Bax, and inhibited oxidative stress-induced apoptotic killing in the HBx-expressing HL-7702 cells. Our findings suggest that HBx exhibits pro-apoptotic effects upon normal liver cells following exposure to oxidative stress by modulating the MPTP gateway.

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“…HBx, a regulatory protein, can stimulate multiple host pathways including p38, ERK, JNK and NF-κB [20, 42, 43]. Large surface protein activated p38 and NF-κB [44, 45], while C-terminally truncated middle surface protein activated ERK2 [46], NF-κB and other pathways [47].…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B Virus Core Antigen Stimulates IL-6 Expression via p38, ERK and NF-κB Pathways in Hepatocytes

Chen

et al. 2017

Cell Physiol Biochem

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Background: Hepatitis B virus (HBV) causes both acute and chronic liver injury. Viral proteins are involved in the pathological progress. Hepatitis B core antigen (HBcAg), a component of viral nucleocapsid, is not only essential for HBV lifecycle, but also exhibits strong immunogenicity. The cytoplasmic location of HBcAg in liver biopsy is associated with liver injury and inflammation, but the exact mechanisms remain to be elaborated. Methods: Huh7, SMMC-7721 and L-02 cells were transfected with pEGFP-N1-HBcAg to establish an intracellular HBcAg expression model. The mRNA and protein levels of Interleukin (IL)-6 were detected by qPCR and ELISA respectively. The signaling pathway-related proteins were investigated by western blot and immunofluorescence assay. Results: HBcAg increased the expression and secretion of IL-6 through activating extracellular signal-related kinase (ERK), p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappa B (NF-κB). These activations can be blocked by specific inhibitors of the three pathways. Conclusions: HBcAg actives p38, ERK1/2 and NF-κB to enhance the production of IL-6 in hepatocytes. This provides a molecular mechanism to explain the association of cytoplasmic HBcAg with severe liver injury and inflammation.

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The role of hepatitis B virus X protein is related to its differential intracellular localization

Cited by 34 publications

References 56 publications

Hepatitis B virus X protein activates the ATM–Chk2 pathway and delays cell cycle progression

Hepatitis B virus X protein activates the ATM–Chk2 pathway and delays cell cycle progression

Hepatitis B virus X protein sensitizes HL-7702 cells to oxidative stress-induced apoptosis through modulation of the mitochondrial permeability transition pore

Hepatitis B Virus Core Antigen Stimulates IL-6 Expression via p38, ERK and NF-κB Pathways in Hepatocytes

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