Hepatitis B Virus-induced hFGL2 Transcription Is Dependent on c-Ets-2 and MAPK Signal Pathway

Han, Meifang; Yan, Weiming; Guo, Wei; Xi, Dong; Zhou, Yifang; Li, Weina; Gao, Sui; Liu, Mingfeng; Levy, Gary; Luo, Xiaoping; Ning, Qin

doi:10.1074/jbc.m806769200

Cited by 46 publications

(35 citation statements)

References 57 publications

(71 reference statements)

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“…We found that MHV-3 infection recruits a larger number of NK cells from the spleen and BM into the liver. Postinfection, we found markedly increased expression of CD69 on liver NK cells, significantly enhanced target cell killing to YAC-1, and increased production from the liver NK cells of IFN-g and TNF-a [potent inhibitors of viral replication, promoters of fgl2/fibroleukin leading to apoptosis, and factors in the pathogenesis of murine and human fulminant hepatitis (23)(24)(25)(26)]. These findings suggest that highly activated liver NK cells and increased levels of cytokines act synergistically to induce BALB/cJ mice FHF post-MHV-3 infection.…”

Section: Discussionmentioning

confidence: 99%

Increased Killing of Liver NK Cells by Fas/Fas Ligand and NKG2D/NKG2D Ligand Contributes to Hepatocyte Necrosis in Virus-Induced Liver Failure

Zou¹,

Chen²,

Han³

et al. 2009

The Journal of Immunology

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118

113

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The role of liver NK cells in virus-induced severe viral hepatitis and, subsequently, hepatic failure is not well defined. In this study, we investigated the role of liver NK cells in the development of hepatocyte necrosis in fulminant hepatic failure (FHF)and acute-on-chronic liver failure (ACLF) because of viral infection. A mouse model of FHF induced by murine hepatitis virus strain 3 (MHV-3) was used to study the role of liver NK cells. Samples from patients with hepatitis B virus-related ACLF (HBV-ACLF) were examined. After MHV-3 infection, the number of NK cells in livers of BALB/cJ mice increased markedly, peaked at 48 h postinfection, and remained at a high level until sacrifice. In peripheral blood, spleen, and bone marrow, this number decreased significantly. Expression of CD69, cytotoxic activity, and intracellular IFN-γ and TNF-α production by liver NK cells at 48 h postinfection were all significantly upregulated. Depletion of NK cells 24 h post-MHV-3 infection increased the mice survival from 0 of 18 (0%) to 4 of 18 (22.2%). Highly activated liver NK cells were cytotoxic to MHV-3-infected hepatocytes and this effect was markedly inhibited by anti-Fas ligand (FasL) plus anti-NKG2D mAbs. Furthermore, the accumulation of hepatic NK cells and increased expression of FasL and natural cytotoxicity receptors (NKp30 and NKp46) on the peripheral NK cells from patients with HBV-ACLF were correlated with disease progression. These results indicate NK cells play a pivotal role in the pathogenesis of FHF and HBV-ACLF, in which process Fas/FasL and NKG2D/NKG2D ligand pathway contribute to the liver NK cell-mediated hepatocyte injury.

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Section: Discussionmentioning

confidence: 99%

Increased Killing of Liver NK Cells by Fas/Fas Ligand and NKG2D/NKG2D Ligand Contributes to Hepatocyte Necrosis in Virus-Induced Liver Failure

Zou¹,

Chen²,

Han³

et al. 2009

The Journal of Immunology

Self Cite

118

113

View full text Add to dashboard Cite

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“…5E). It is well known that expression of Ets-2 is regulated by the Erk1/2 pathway, and translocation of Ets-2 is also modulated by MAPKs (33). Thus, we examined the effects of MAPK inhibitors on the expression and low pH-mediated translocation of Ets-2.…”

Section: Jnk Is Involved In Low Ph-mediated Stabilin-1 Expression-mentioning

confidence: 99%

Extracellular Low pH Modulates Phosphatidylserine-dependent Phagocytosis in Macrophages by Increasing Stabilin-1 Expression

Park

Bae

Kim

et al. 2012

Journal of Biological Chemistry

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Background: Extracellular acidification is a feature of inflammation loci in which apoptotic cell clearance is necessary for inflammation resolution. Results: Low pH increases stabilin-1 expression and stabilin-1-mediated phagocytosis in macrophages. Conclusion: Extracellular acidification up-regulates stabilin-1 expression in macrophages, thereby modulating the phagocytic capacity of macrophages. Significance: This study should help elucidate the molecular mechanism regarding stabilin-1 regulation and apoptotic cell clearance in acidic environments.

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“…Besides the class I PI3K/AKT/mTOR and class III PI3K/beclin-1 signaling pathways, MAPKs (ERK, p38, and JNK) may also play an important role in autophagy induction (21), while HBx, as a multifunctional protein, is well known for its role in the regulation of diverse signaling pathways (41,42). We therefore further examined the contribution of MAPKs to HBx-induced autophagosome formation.…”

mentioning

confidence: 99%

Reactive Oxygen Species-Mediated c-Jun NH ₂ -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

Zhong

Shu

Dai

et al. 2017

J Virol

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Autophagy is closely associated with the regulation of hepatitis B virus (HBV) replication. HBV X protein (HBx), a multifunctional regulator in HBV-associated biological processes, has been demonstrated to be crucial for autophagy induction by HBV. However, the molecular mechanisms of autophagy induction by HBx, especially the signaling pathways involved, remain elusive. In the present investigation, we demonstrated that HBx induced autophagosome formation independently of the class I phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway. In contrast, the class III PI3K(VPS34)/beclin-1 pathway was revealed to be critical for HBx-induced autophagosome formation. Further study showed that HBx did not affect the level of VPS34 and beclin-1 expression but inhibited beclin-1/Bcl-2 association, and c-Jun NH2-terminal kinase (JNK) signaling was found to be important for this process. Moreover, it was found that HBx treatment led to the generation of reactive oxygen species (ROS), and inhibition of ROS activity abrogated both JNK activation and autophagosome formation. Of importance, ROS-JNK signaling was also revealed to play an important role in HBV-induced autophagosome formation and subsequent HBV replication. These data may provide deeper insight into the mechanisms of autophagy induction by HBx and help in the design of new therapeutic strategies against HBV infection.IMPORTANCE HBx plays a key role in diverse HBV-associated biological processes, including autophagy induction. However, the molecular mechanisms of autophagy induction by HBx, especially the signaling pathways involved, remain elusive. In the present investigation, we found that HBx induced autophagy independently of the class I PI3K/AKT/mTOR signaling pathway, while the class III PI3K(VPS34)/beclin-1 pathway was revealed to be crucial for this process. Further data showed that ROS-JNK activation by HBx resulted in the release of beclin-1 from its association with Bcl-2 to form a complex with VPS34, thus enhancing autophagosome formation. Of importance, ROS-JNK signaling was also demonstrated to be critical for HBV replication via regulation of autophagy induction. These data help to elucidate the molecular mechanisms of autophagy induction by HBx/HBV and might be useful for designing novel therapeutic approaches to HBV infection.KEYWORDS HBV X protein, autophagy, signaling pathway, viral replication H epatitis B virus (HBV) is an important human pathogen that can cause a wide spectrum of liver diseases, including hepatitis, liver cirrhosis, and hepatocellular carcinoma (1, 2). The HBV genome is about 3.2 kb in length, carrying four genes named

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Hepatitis B Virus-induced hFGL2 Transcription Is Dependent on c-Ets-2 and MAPK Signal Pathway

Cited by 46 publications

References 57 publications

Increased Killing of Liver NK Cells by Fas/Fas Ligand and NKG2D/NKG2D Ligand Contributes to Hepatocyte Necrosis in Virus-Induced Liver Failure

Increased Killing of Liver NK Cells by Fas/Fas Ligand and NKG2D/NKG2D Ligand Contributes to Hepatocyte Necrosis in Virus-Induced Liver Failure

Extracellular Low pH Modulates Phosphatidylserine-dependent Phagocytosis in Macrophages by Increasing Stabilin-1 Expression

Reactive Oxygen Species-Mediated c-Jun NH ₂ -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

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Hepatitis B Virus-induced hFGL2 Transcription Is Dependent on c-Ets-2 and MAPK Signal Pathway

Cited by 46 publications

References 57 publications

Increased Killing of Liver NK Cells by Fas/Fas Ligand and NKG2D/NKG2D Ligand Contributes to Hepatocyte Necrosis in Virus-Induced Liver Failure

Increased Killing of Liver NK Cells by Fas/Fas Ligand and NKG2D/NKG2D Ligand Contributes to Hepatocyte Necrosis in Virus-Induced Liver Failure

Extracellular Low pH Modulates Phosphatidylserine-dependent Phagocytosis in Macrophages by Increasing Stabilin-1 Expression

Reactive Oxygen Species-Mediated c-Jun NH 2 -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

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Reactive Oxygen Species-Mediated c-Jun NH ₂ -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction