Activation of the Ras/Raf/MEK Pathway Facilitates Hepatitis C Virus Replication via Attenuation of the Interferon-JAK-STAT Pathway

Zhang, Qi; Gong, Rui; Qu, Jing; Zhou, Yijing; Liu, Weiyong; Chen, Mingzhou; Liu, Yingle; Zhu, Ying

doi:10.1128/jvi.00688-11

Cited by 68 publications

(62 citation statements)

References 75 publications

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“…Several studies have indicated that these factors, including those encoding OAS and PKR, could inhibit HCV infection (32,43,44,63,64). In the present study, we showed that overexpression of Set7 inhibited virusinduced IFN-a, IFN-b, PKR, and OAS activation; however, both knockdown of Set7 and inhibition of Set7 enzymatic activity demonstrated reverse effects.…”

Section: Discussionsupporting

confidence: 47%

“…Presently, IFN-a alone or in combination with ribavirin is the most common and effective therapy strategy for HCV (51, (32,53). Our above results showed that the SeVinduced mRNA of both PKR and OAS were inhibited by Set7.…”

Section: Set7 Suppresses the Expression Of Ifn-induced Downstream Effmentioning

confidence: 57%

“…These results are in complete agreement with our data. Additionally, Zhang et al (32) have suggested that the Ras/Raf/MEK pathway negatively regulates the JAK/ STAT pathway by downregulating the expression of IFNAR1 and IFNAR2. We also found that the phosphorylation level of ERK (an indicator of activation of the Ras/Raf/MEK pathway) is upregulated by Set7 (T. Han and Y. Wan, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

“…Renilla luciferase activities were used as internal controls in the Dual-Luciferase assay system. Virus RNA transcription in vitro and Renilla luciferase activity of FL-J6/JFH59C19Rluc2AUbi were performed as described previously (32). FL-J6/JFH59C19Rluc2Aubi was provided by Dr. Charles M. Rice of Rockefeller University.…”

Section: Cell Transfection and Luciferase Reporter Gene Assaymentioning

confidence: 99%

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Set7 Facilitates Hepatitis C Virus Replication via Enzymatic Activity–Dependent Attenuation of the IFN-Related Pathway

Han

Wang

Zhao

et al. 2015

The Journal of Immunology

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Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, usually resulting in persistent infection involving hepatic steatosis, cirrhosis, and hepatocellular carcinoma via escape of the host’s immune response. Set7 is a lysine-specific methyltransferase that is involved in gene regulation and virus replication. However, the mechanism underlying the immune evasion between HCV and Set7 is not well understood. In this study, we observed that the expression of Set7 in Huh7.5.1 cells was upregulated by HCV infection, and high levels of Set7 expression were also found in the sera, PBMCs, and liver tissue of HCV patients relative to healthy individuals. Further investigation showed that Set7 enhanced HCV replication in an enzymatic activity–dependent manner. Moreover, our data showed that Set7 decreased the expression of virus-induced IFN and IFN-related effectors, such as dsRNA-activated protein kinase and 2′,5′-oligoadenylate synthetase. Further investigation suggested that Set7 suppressed the endogenous IFN expression by reducing the nuclear translocation of IFN regulatory factor 3/7 and the p65 subunit of NF-κB and reduced IFN-induced dsRNA-activated protein kinase and 2′,5′-oligoadenylate synthetase via attenuation of the phosphorylation of STAT1 and STAT2. Additionally, IFN receptors, including IFNAR1 and IFNAR2, which are located upstream of the JAK/STAT pathway, were reduced by Set7. Taken together, our results reveal that Set7 facilitates HCV replication through the attenuation of IFN signaling pathways and IFN-related effectors.

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Section: Discussionsupporting

confidence: 47%

Section: Set7 Suppresses the Expression Of Ifn-induced Downstream Effmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Cell Transfection and Luciferase Reporter Gene Assaymentioning

confidence: 99%

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Set7 Facilitates Hepatitis C Virus Replication via Enzymatic Activity–Dependent Attenuation of the IFN-Related Pathway

Han

Wang

Zhao

et al. 2015

The Journal of Immunology

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“…In the ligand-independent pathway, the unfolded-protein response (UPR) activates p38 kinase, which subsequently phosphorylates IFNAR1 at Ser532 (35)(36)(37)(38). We previously reported that extracellular signal-regulated kinase (ERK) is involved in the degradation of IFNAR1 (39,40). Here, the signaling pathways that participated in the MMP-9-mediated degradation of IFNAR1 were evaluated in HepG2 cells transfected with pCMV-Tag2B-MMP-9 and treated with the signaling component inhibitors SB203580 (p38 mitogen-activated protein kinase [MAPK] inhibitor), U0126 (ERK1/2 inhibitor), and PD98059 (MEK inhibitor).…”

Section: Resultsmentioning

confidence: 99%

Matrix Metalloproteinase 9 Facilitates Hepatitis B Virus Replication through Binding with Type I Interferon (IFN) Receptor 1 To Repress IFN/JAK/STAT Signaling

Chen

et al. 2017

J Virol

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Hepatitis B virus (HBV) infection may cause acute hepatitis B, chronic hepatitis B (CHB), liver cirrhosis, and hepatocellular carcinoma (HCC). However, the mechanisms by which HBV evades host immunity and maintains chronic infection are largely unknown. Here, we revealed that matrix metalloproteinase 9 (MMP-9) is activated in peripheral blood mononuclear cells (PBMCs) of HBV-infected patients, and HBV stimulates MMP-9 expression in macrophages and PBMCs isolated from healthy individuals. MMP-9 plays important roles in the breakdown of the extracellular matrix and in the facilitation of tumor progression, invasion, metastasis, and angiogenesis. MMP-9 also regulates respiratory syncytial virus (RSV) replication, but the mechanism underlying such regulation is unknown. We further demonstrated that MMP-9 facilitates HBV replication by repressing the interferon (IFN)/Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, IFN action, STAT1/2 phosphorylation, and IFN-stimulated gene (ISG) expression. Moreover, MMP-9 binds to type I IFN receptor 1 (IFNAR1) and facilitates IFNAR1 phosphorylation, ubiquitination, subcellular distribution, and degradation to interfere with the binding of IFANR1 to IFN-␣. Thus, we identified a novel positive-feedback regulation loop between HBV replication and MMP-9 production. On one hand, HBV activates MMP-9 in infected patients and leukocytes. On the other hand, MMP-9 facilitates HBV replication through repressing IFN/JAK/STAT signaling, IFNAR1 function, and IFN-␣ action. Therefore, HBV may take the advantage of MMP-9 function to establish or maintain chronic infection. IMPORTANCE Hepatitis B virus (HBV) infection may cause chronic hepatitis B (CHB)and hepatocellular carcinoma (HCC). However, the mechanisms by which HBV maintains chronic infection are largely unknown. Matrix metalloproteinase 9 (MMP-9) plays important roles in the facilitation of tumor progression, invasion, metastasis, and angiogenesis. However, the effects of MMP-9 on HBV replication and pathogenesis are not known. This study reveals that MMP-9 expression is activated in patients with CHB, and HBV stimulates MMP-9 production in PBMCs and macrophages. More interestingly, MMP-9 in turn promotes HBV replication through suppressing IFN-␣ action. Moreover, MMP-9 interacts with type I interferon receptor 1 (IFNAR1) to disturb the binding of IFN-␣ to IFNAR1 and facilitate the phosphorylation, ubiquitination, subcellular distribution, and degradation of IFNAR1. Therefore, these results discover a novel role of MMP-9 in viral replication and reveal a new mechanism by which HBV evades host immunity to maintain persistent infection.KEYWORDS hepatitis B virus, interferon/Janus kinase/signal transducers and activators of transcription pathway, matrix metalloproteinase 9, type I IFN receptor 1

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Nonstructural protein 5B promotes degradation of the NORE1A tumor suppressor to facilitate hepatitis C virus replication

et al. 2017

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Hepatitis C infection is a common risk factor for the development of liver cancer. The molecular mechanisms underlying this effect are only partially understood. Here we show that the HCV protein NS5B directly binds to the tumor suppressor NORE1A (RASSF5) and promotes its proteosomal degradation. In addition, we show that NORE1A co-localizes to sites of HCV viral replication and suppresses the process. Thus, NORE1A has anti-viral activity which is specifically antagonized by NS5B. Moreover, the suppression of NORE1A protein levels correlated almost perfectly with elevation of Ras activity in primary human samples. Therefore, NORE1A inactivation by NS5B may be essential for maximal HCV replication and may make a major contribution to HCV induced liver cancer by shifting Ras signaling away from pro-senescent/apoptotic signaling pathways. Conclusion HCV uses NS5B to specifically suppress NORE1A facilitating viral replication and elevated Ras signaling.

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Activation of the Ras/Raf/MEK Pathway Facilitates Hepatitis C Virus Replication via Attenuation of the Interferon-JAK-STAT Pathway

Cited by 68 publications

References 75 publications

Set7 Facilitates Hepatitis C Virus Replication via Enzymatic Activity–Dependent Attenuation of the IFN-Related Pathway

Set7 Facilitates Hepatitis C Virus Replication via Enzymatic Activity–Dependent Attenuation of the IFN-Related Pathway

Matrix Metalloproteinase 9 Facilitates Hepatitis B Virus Replication through Binding with Type I Interferon (IFN) Receptor 1 To Repress IFN/JAK/STAT Signaling

Nonstructural protein 5B promotes degradation of the NORE1A tumor suppressor to facilitate hepatitis C virus replication

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