乙型肝炎病毒多聚酶抑制Ⅰ型干扰素诱生机制的研究
摘要
乙型肝炎病毒目前依然是影响广大发展中国家人民健康的重要病原体。据统计,全球仍然有3亿5千万人感染乙型肝炎病毒,其中我国携带乙型肝炎病毒人数约占23%。尽管大规模的计划内疫苗接种已经大大降低了新生儿感染乙型肝炎病毒的风险,但是对已经感染乙型肝炎病毒的广大人群目前依然缺乏十分有效的药物以清除病毒。目前临床上使用干扰素a可以有效抑制乙型肝炎病毒复制,但是仅对不到30%的患者有效。遗憾的是,造成大部分乙型肝炎患者干扰素抵抗的分子机制至今仍不是十分清楚。
I型干扰素(包括干扰素α[与干扰素β)是天然免疫的重要有机组成部分,在对抗并清除病毒性感染中发挥不可替代的作用。研究表明I型干扰素的诱生依赖于宿主细胞模式识别受体识别相关病毒成分并启动相关信号通路。然而,长期的生存压力促使以寄生为唯一生存方式的病毒进化出相应的对抗机制以克服I型干扰素的诱生从而建立并维持长期感染状态。研究发现慢性乙型肝炎患者体内pDC细胞合成干扰素α能力明显减弱。已有研究报道肝细胞在病毒或有关分子刺激下可产生I型干扰素,但乙肝病毒感染肝细胞后可在细胞内建立持续复制,提示病毒也能拮抗肝细胞干扰素的诱生或作用。而且有报道的确证实HBsAg、HBeAg以及病毒颗粒可以抑制Toll样受体介导的I型干扰素以及炎性因子的诱生。但是对于乙型肝炎病毒对肝细胞内RIG-I介导I型干扰素诱生途径是否存在抑制作用及机制目前了解不多。
为此,本研究通过双荧光报告体系筛查定位于胞浆的病毒蛋白成分(Core蛋白,X蛋白以及Pol蛋白)对干扰素β启动子活性的影响,发现Pol蛋白对干扰素p启动子存在抑制现象。在此基础上,通过实时定量PCR技术以及ELISA技术检测了Pol蛋白对内源性干扰素p诱生的影响。结果发现Pol可以剂量依赖形式抑制内源性干扰素p的诱生。同时,病毒攻击保护实验证实Pol蛋白可以通过抑制PH5CH8诱生干扰素p从而消弱其保护Vero细胞抵抗NDV-GFP的感染能力。上述研究结果确认了乙型肝炎病毒Pol蛋白对原代肝细胞系PH5CH8干扰素β诱生的抑制效应。
为了揭示Pol蛋白抑制干扰素β诱生的分子机制,将Pol与I型干扰素诱生通路中一系列关键分子共转染293T细胞,通过监测干扰素β的启动子活性变化来锁定Pol蛋白抑制I型干扰素诱生的环节。结果显示Pol可以抑制蛋白激酶TBK1/IKKε及其上游所有关键分子对干扰素β启动子的活化能力,但对干扰素调节因子3(IRF3)永久活化突变体没有抑制效应。为此,将Pol抑制I型干扰素诱生的环节锁定在TBK1/IKKε水平。进一步检测发现Pol蛋白可以抑制内源性IRF3活化,但是并未检测到Pol与IRF3存在直接相互作用,由此推测Pol可能通过某种间接途径抑制内源性IRF3的活化。
由于有文献报道DDX3与TBK1/IKKε存在相互作用并参与TBK1/IKKε诱生I型干扰素,而且DDX3亦可以结合Pol抑制乙型肝炎病毒逆转录,故通过免疫共沉淀技术比较Pol表达对DDX3与TBK1/IKKε相互作用的影响。结果发现Pol表达可以抑制DDX3与TBK1/IKKε相互作用,同时还可以降低TBK1/IKKε对DDX3磷酸化效应。而过表达DDX3可以恢复Pol对I型干扰素的抑制能力,这提示Pol可能通过竞争性结合DDX3、降低TBK1/IKKε与DDX3相互作用机会从而发挥抑制I型干扰素诱生能力。
本研究首次揭示了乙型肝炎病毒多聚酶Pol参与病毒对I型干扰素诱生的抑制作用,锁定其抑制环节发生在TBK1/IKKε水平,并且证实DDX3可能是Pol抑制I型干扰素诱生的靶点。上述结果有助于推动乙型肝炎病毒感染慢性化机制的研究以及新的靶点药物开发。
Molecular Mechanism of TypeⅠInterferon Induction Inhibited by Hepatitis B Virus Polymerase
Hepatitis B virus (HBV) is still one of the most dangerous pathogens jeopardizing public health globally. True, the routine vaccination has significantly decreased the risk of HBV infection in the population of newborn. But few and rare proper approaches can be clinically used to control HBV proliferation in those who have been chronically infected. More sadly,70% of patients with chronic HBV infection have no response to interferon a (IFNa) which is proved to effectively inhibit viral genes expression and proliferation. However, the molecular mechanism remains hazy. Thus, more investigation is needed to undertake to uncover the interplay between HBV and typeⅠIFN.
TypeⅠIFN (including IFNa and IFNβ), playing a critical role in control and clearance of viral infection, can be induced by cellular pattern recognition receptors, such as Toll-like receptors (TLRs), RIG-I like helicases. Once engagement with viral ligands, TLR and RIG-I will recruit specific adaptors, for instance, TRIF, IPS1 and further motivate kinases TBK1/IKKεwhich can phosphorylate and activate interferon regulatory factor 3(IRF3), a key transcriptional factor required for typeⅠIFN production. In addition, DEAD-box helicase DDX3 is also another crucial component in the program of typeⅠIFN induction by TBK1/IKKε.
In the long trajectory of evolution, viruses have developed numerous strategies to avert typeⅠIFN induction. For example, hepatitis C virus encodes NS3A to cleave key adaptors IPS1 and TRIF to sabotage typeⅠIFN synthesis. Similarly, a growing body of evidence also suggests that HBV can abrogate typeⅠIFN. HBV surface antigen (HBsAg), e antigen (HBeAg) and virions have been reported to almost completely suppress TLR-mediated antiviral activity and cytokine induction in murine liver parenchymal cells, indicating that HBV can counteract the TLR-mediated innate immune response. However, little is known about whether and how HBV disturbs cytoplasmic RIG-I-mediated IFNβinduction in human hepatocytes:
In this study, we performed a functional screen assay to determine whether cytoplasmic viral proteins (including core, X and Pol) interfere with IFNP induction triggered by Sendai virus (SeV) and Newcastle Disease virus (NDV) challenge in primary human hepatocytes PH5CH8. Our results showed that only Pol inhibited the activation of IFNβpromoter in response to SeV and NDV infection though the expression of Core or X was higher than Pol. Interestingly, Pol also inhibited the activation of TLR3 signaling when poly(I:C) was directly added into cell culture, suggesting that the site of inhibition by Pol could be at the lower level in typeⅠIFN induction axis. Furthermore, we excluded the possibility of non-specific effects on IFNβpromoter using the unrelated p53 promoter reporter system. To further characterize the inhibitory effect of Pol, the induction of endogenous IFNβin PH5CH8 cells with or without Pol expression was examined using real-time quantitative PCR and ELISA. The data showed Pol could impede endogenous IFNβinduction in a dose-dependent manner. In addition, ectopic expression of Pol impaired the transferrable antiviral capacity of primary hepatocytes PH5CH8 in response to NDV infection which can protect Vero cells from NDV-GFP infection via secretion of IFNβ.
To uncover the level at which Pol interferes with typeⅠIFN induction, 293T cells were co-tranfected with key molecules in typeⅠIFN induction axis and Pol. We found that Pol blocked the activation of IFNβpromoter triggered by all key molecules tested except IRF3-5D mutant. Moreover, we also determined the effect of Pol on the activation of endogenous IRF3 using native-PAGE, western blot and immunofluorescence. Our results showed that Pol could abrogate endogenous IRF3 activation by SeV. Unfortunately, we didn't detect the direct interaction between Pol and IRF3, implying that the inhibitory effect of Pol on IRF3 activation is indirect. Thus, we defined the inhibition at the level of TBK1/IKKε.
Given that DDX3 is involved in TBK1/IKKεmediated typeⅠIFN induction and also participates in inhibition of HBV reverse transcription via interaction with Pol, we speculated that DDX3 could be the target in the inhibition of typeⅠIFN by Pol. Immunoprecipitation assay revealed that less of TBK1/IKKεwas probed in the DDX3 immunoprecipitation complex in the cells with pol expression than in those without pol expression. However, over-expression of DDX3 restored the inhibition of SeV or TBK1 mediated induction of typeⅠIFN by Pol. It indicates that Pol can dampen the interaction between TBK1/IKKεand DDX3 through the competitive binding to DDX3.
Taken together, these findings reveal a novel role of HBV polymerase in HBV counteraction of IFNβproduction in human hepatocytes
I型干扰素(包括干扰素α[与干扰素β)是天然免疫的重要有机组成部分,在对抗并清除病毒性感染中发挥不可替代的作用。研究表明I型干扰素的诱生依赖于宿主细胞模式识别受体识别相关病毒成分并启动相关信号通路。然而,长期的生存压力促使以寄生为唯一生存方式的病毒进化出相应的对抗机制以克服I型干扰素的诱生从而建立并维持长期感染状态。研究发现慢性乙型肝炎患者体内pDC细胞合成干扰素α能力明显减弱。已有研究报道肝细胞在病毒或有关分子刺激下可产生I型干扰素,但乙肝病毒感染肝细胞后可在细胞内建立持续复制,提示病毒也能拮抗肝细胞干扰素的诱生或作用。而且有报道的确证实HBsAg、HBeAg以及病毒颗粒可以抑制Toll样受体介导的I型干扰素以及炎性因子的诱生。但是对于乙型肝炎病毒对肝细胞内RIG-I介导I型干扰素诱生途径是否存在抑制作用及机制目前了解不多。
为此,本研究通过双荧光报告体系筛查定位于胞浆的病毒蛋白成分(Core蛋白,X蛋白以及Pol蛋白)对干扰素β启动子活性的影响,发现Pol蛋白对干扰素p启动子存在抑制现象。在此基础上,通过实时定量PCR技术以及ELISA技术检测了Pol蛋白对内源性干扰素p诱生的影响。结果发现Pol可以剂量依赖形式抑制内源性干扰素p的诱生。同时,病毒攻击保护实验证实Pol蛋白可以通过抑制PH5CH8诱生干扰素p从而消弱其保护Vero细胞抵抗NDV-GFP的感染能力。上述研究结果确认了乙型肝炎病毒Pol蛋白对原代肝细胞系PH5CH8干扰素β诱生的抑制效应。
为了揭示Pol蛋白抑制干扰素β诱生的分子机制,将Pol与I型干扰素诱生通路中一系列关键分子共转染293T细胞,通过监测干扰素β的启动子活性变化来锁定Pol蛋白抑制I型干扰素诱生的环节。结果显示Pol可以抑制蛋白激酶TBK1/IKKε及其上游所有关键分子对干扰素β启动子的活化能力,但对干扰素调节因子3(IRF3)永久活化突变体没有抑制效应。为此,将Pol抑制I型干扰素诱生的环节锁定在TBK1/IKKε水平。进一步检测发现Pol蛋白可以抑制内源性IRF3活化,但是并未检测到Pol与IRF3存在直接相互作用,由此推测Pol可能通过某种间接途径抑制内源性IRF3的活化。
由于有文献报道DDX3与TBK1/IKKε存在相互作用并参与TBK1/IKKε诱生I型干扰素,而且DDX3亦可以结合Pol抑制乙型肝炎病毒逆转录,故通过免疫共沉淀技术比较Pol表达对DDX3与TBK1/IKKε相互作用的影响。结果发现Pol表达可以抑制DDX3与TBK1/IKKε相互作用,同时还可以降低TBK1/IKKε对DDX3磷酸化效应。而过表达DDX3可以恢复Pol对I型干扰素的抑制能力,这提示Pol可能通过竞争性结合DDX3、降低TBK1/IKKε与DDX3相互作用机会从而发挥抑制I型干扰素诱生能力。
本研究首次揭示了乙型肝炎病毒多聚酶Pol参与病毒对I型干扰素诱生的抑制作用,锁定其抑制环节发生在TBK1/IKKε水平,并且证实DDX3可能是Pol抑制I型干扰素诱生的靶点。上述结果有助于推动乙型肝炎病毒感染慢性化机制的研究以及新的靶点药物开发。
Molecular Mechanism of TypeⅠInterferon Induction Inhibited by Hepatitis B Virus Polymerase
Hepatitis B virus (HBV) is still one of the most dangerous pathogens jeopardizing public health globally. True, the routine vaccination has significantly decreased the risk of HBV infection in the population of newborn. But few and rare proper approaches can be clinically used to control HBV proliferation in those who have been chronically infected. More sadly,70% of patients with chronic HBV infection have no response to interferon a (IFNa) which is proved to effectively inhibit viral genes expression and proliferation. However, the molecular mechanism remains hazy. Thus, more investigation is needed to undertake to uncover the interplay between HBV and typeⅠIFN.
TypeⅠIFN (including IFNa and IFNβ), playing a critical role in control and clearance of viral infection, can be induced by cellular pattern recognition receptors, such as Toll-like receptors (TLRs), RIG-I like helicases. Once engagement with viral ligands, TLR and RIG-I will recruit specific adaptors, for instance, TRIF, IPS1 and further motivate kinases TBK1/IKKεwhich can phosphorylate and activate interferon regulatory factor 3(IRF3), a key transcriptional factor required for typeⅠIFN production. In addition, DEAD-box helicase DDX3 is also another crucial component in the program of typeⅠIFN induction by TBK1/IKKε.
In the long trajectory of evolution, viruses have developed numerous strategies to avert typeⅠIFN induction. For example, hepatitis C virus encodes NS3A to cleave key adaptors IPS1 and TRIF to sabotage typeⅠIFN synthesis. Similarly, a growing body of evidence also suggests that HBV can abrogate typeⅠIFN. HBV surface antigen (HBsAg), e antigen (HBeAg) and virions have been reported to almost completely suppress TLR-mediated antiviral activity and cytokine induction in murine liver parenchymal cells, indicating that HBV can counteract the TLR-mediated innate immune response. However, little is known about whether and how HBV disturbs cytoplasmic RIG-I-mediated IFNβinduction in human hepatocytes:
In this study, we performed a functional screen assay to determine whether cytoplasmic viral proteins (including core, X and Pol) interfere with IFNP induction triggered by Sendai virus (SeV) and Newcastle Disease virus (NDV) challenge in primary human hepatocytes PH5CH8. Our results showed that only Pol inhibited the activation of IFNβpromoter in response to SeV and NDV infection though the expression of Core or X was higher than Pol. Interestingly, Pol also inhibited the activation of TLR3 signaling when poly(I:C) was directly added into cell culture, suggesting that the site of inhibition by Pol could be at the lower level in typeⅠIFN induction axis. Furthermore, we excluded the possibility of non-specific effects on IFNβpromoter using the unrelated p53 promoter reporter system. To further characterize the inhibitory effect of Pol, the induction of endogenous IFNβin PH5CH8 cells with or without Pol expression was examined using real-time quantitative PCR and ELISA. The data showed Pol could impede endogenous IFNβinduction in a dose-dependent manner. In addition, ectopic expression of Pol impaired the transferrable antiviral capacity of primary hepatocytes PH5CH8 in response to NDV infection which can protect Vero cells from NDV-GFP infection via secretion of IFNβ.
To uncover the level at which Pol interferes with typeⅠIFN induction, 293T cells were co-tranfected with key molecules in typeⅠIFN induction axis and Pol. We found that Pol blocked the activation of IFNβpromoter triggered by all key molecules tested except IRF3-5D mutant. Moreover, we also determined the effect of Pol on the activation of endogenous IRF3 using native-PAGE, western blot and immunofluorescence. Our results showed that Pol could abrogate endogenous IRF3 activation by SeV. Unfortunately, we didn't detect the direct interaction between Pol and IRF3, implying that the inhibitory effect of Pol on IRF3 activation is indirect. Thus, we defined the inhibition at the level of TBK1/IKKε.
Given that DDX3 is involved in TBK1/IKKεmediated typeⅠIFN induction and also participates in inhibition of HBV reverse transcription via interaction with Pol, we speculated that DDX3 could be the target in the inhibition of typeⅠIFN by Pol. Immunoprecipitation assay revealed that less of TBK1/IKKεwas probed in the DDX3 immunoprecipitation complex in the cells with pol expression than in those without pol expression. However, over-expression of DDX3 restored the inhibition of SeV or TBK1 mediated induction of typeⅠIFN by Pol. It indicates that Pol can dampen the interaction between TBK1/IKKεand DDX3 through the competitive binding to DDX3.
Taken together, these findings reveal a novel role of HBV polymerase in HBV counteraction of IFNβproduction in human hepatocytes
引文
[1]M.J. Alter, Epidemiology of hepatitis B in Europe and worldwide, J Hepatol 39 Suppl 1 (2003) S64-69.
[2]S.A. Gonzalez, E.B. Keeffe, Chronic viral hepatitis:epidemiology, molecular biology, and antiviral therapy, Front Biosci 16 (2011) 225-250.
[3]G. Fattovich, F. Bortolotti, F. Donato, Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors, J Hepatol 48 (2008) 335-352.
[4]P. Bonanni, G. Pesavento, S. Boccalini, A. Bechini, Perspectives of public health: present and foreseen impact of vaccination on the epidemiology of hepatitis B, J Hepatol 39 Suppl 1 (2003) S224-229.
[5]F. Zoulim, Hepatitis B virus resistance to antivirals:clinical implications and management, J Hepatol 39 Suppl 1 (2003) S133-138.
[6]M. van Zonneveld, P. Honkoop, B.E. Hansen, H.G. Niesters, S. Darwish Murad, R.A. de Man, S.W. Schalm, H.L. Janssen, Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B, Hepatology 39 (2004) 804-810.
[7]C. Seeger, W.S. Mason, Hepatitis B virus biology, Microbiol Mol Biol Rev 64 (2000)51-68.
[8]F. Zoulim, New insight on hepatitis B virus persistence from the study of intrahepatic viral cccDNA, J Hepatol 42 (2005) 302-308.
[9]X. Lu, T. Block, Study of the early steps of the Hepatitis B Virus life cycle, Int J Med Sci 1(2004) 21-33.
[10]C.M. Bremer, I. Sominskaya, D. Skrastina, P. Pumpens, A.A. El Wahed, U. Beutling, R. Frank, H.J. Fritz, G. Hunsmann, W.H. Gerlich, D. Glebe, N-terminal myristoylation-dependent masking of neutralizing epitopes in the preS1 attachment site of hepatitis B virus, J Hepatol (2010).
[11]D. Glebe, S. Urban, E.V. Knoop, N. Cag, P. Krass, S. Grun, A. Bulavaite, K. Sasnauskas, W.H. Gerlich, Mapping of the hepatitis B virus attachment site by use of infection-inhibiting preS1 lipopeptides and tupaia hepatocytes, Gastroenterology 129 (2005) 234-245.
[12]S. Benhenda, D. Cougot, M.A. Buendia, C. Neuveut, Hepatitis B virus X protein molecular functions and its role in virus life cycle and pathogenesis, Adv Cancer Res 103 (2009) 75-109.
[13]S.L. McClain, A.J. Clippinger, R. Lizzano, M.J. Bouchard, Hepatitis B virus replication is associated with an HBx-dependent mitochondrion-regulated increase in cytosolic calcium levels, J Virol 81 (2007) 12061-12065.
[14]J. Lucifora, S. Arzberger, D. Durantel, L. Belloni, M. Strubin, M. Levrero, F. Zoulim, O. Hantz, U. Protzer, Hepatitis B Virus X protein is essential to initiate and maintain virus replication after infection, J Hepatol (2011).
[15]S. Akira, S. Uematsu, O. Takeuchi, Pathogen recognition and innate immunity, Cell 124 (2006) 783-801.
[16]L.R. Sabin, S.L. Hanna, S. Cherry, Innate antiviral immunity in Drosophila, Curr Opin Immunol 22 (2010) 4-9.
[17]D.M. Andrews, M.J. Estcourt, C.E. Andoniou, M.E. Wikstrom, A. Khong, V. Voigt, P. Fleming, H. Tabarias, G.R. Hill, R.G. van der Most, A.A. Scalzo, M.J. Smyth, M.A. Degli-Esposti, Innate immunity defines the capacity of antiviral T cells to limit persistent infection, J Exp Med 207 (2010) 1333-1343.
[18]W.L. Chang, P.A. Barry, Attenuation of innate immunity by cytomegalovirus IL-10 establishes a long-term deficit of adaptive antiviral immunity, Proc Natl Acad Sci U S A 107 (2010) 22647-22652.
[19]J.E. Durbin, A. Fernandez-Sesma, C.K. Lee, T.D. Rao, A.B. Frey, T.M. Moran, S. Vukmanovic, A. Garcia-Sastre, D.E. Levy, Type ⅠIFN modulates innate and specific antiviral immunity, J Immunol 164 (2000) 4220-4228.
[20]G. Trinchieri, Type I interferon:friend or foe?, J Exp Med 207 (2010) 2053-2063.
[21]S. Akira, Pathogen recognition by innate immunity and its signaling, Proc Jpn Acad Phys SerB Biol Sci 85 (2009) 143-156.
[22]L.A. O'Neill, A.G. Bowie, Sensing and signaling in antiviral innate immunity, Curr Biol 20 (2010) R328-333.
[23]A. Sabbah, T.H. Chang, R. Harnack, V. Frohlich, K. Tominaga, P.H. Dube, Y. Xiang, S. Bose, Activation of innate immune antiviral responses by Nod2, Nature Immunol 10 (2009) 1073-1080.
[24]V.A. Rathinam, Z. Jiang, S.N. Waggoner, S. Sharma, L.E. Cole, L. Waggoner, S.K. Vanaja, B.G. Monks, S. Ganesan, E. Latz, V. Hornung, S.N. Vogel, E. Szomolanyi-Tsuda, K.A. Fitzgerald, The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses, Nature Immunol 11 (2010)395-402.
[25]H. Kato, S. Sato, M. Yoneyama, M. Yamamoto, S. Uematsu, K. Matsui, T. Tsujimura, K. Takeda, T. Fujita, O. Takeuchi, S. Akira, Cell type-specific involvement of RIG-I in antiviral response, Immunity 23 (2005) 19-28.
[26]K. Honda, T. Taniguchi, IRFs:master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors, Nature Rev Immunol 6 (2006) 644-658.
[27]M.J. Servant, N. Grandvaux, J. Hiscott, Multiple signaling pathways leading to the activation of interferon regulatory factor 3, Biochem Pharmacol 64 (2002) 985-992.
[28]W. Zeng, M. Xu, S. Liu, L. Sun, Z.J. Chen, Key role of Ubc5 and lysine-63 polyubiquitination in viral activation of IRF3, Mol Cell 36 (2009) 315-325.
[29]L. Sun, S. Liu, Z.J. Chen, SnapShot:pathways of antiviral innate immunity, Cell 140 (2010) 436-436 e432.
[30]T. Taniguchi, A. Takaoka, The interferon-alpha/beta system in antiviral responses: a multimodal machinery of gene regulation by the IRF family of transcription factors, Curr Opin Immunol 14 (2002) 111-116.
[31]A.K. Erickson, M. Gale, Jr., Regulation of interferon production and innate antiviral immunity through translational control of IRF-7, Cell Res 18 (2008) 433-435.
[32]C.R. Roy, E.S. Mocarski, Pathogen subversion of cell-intrinsic innate immunity, Nat Immunol 8 (2007) 1179-1187.
[33]L.M. Hook, H.M. Friedman, Subversion of innate and adaptive immunity: immune evasion from antibody and complement, in:A. Arvin, G. Campadelli-Fiume, E. Mocarski, P.S. Moore, B. Roizman, R. Whitley, K. Yamanishi (Eds.), Human Herpesviruses:Biology, Therapy, and Immunoprophylaxis, Cambridge,2007.
[34]A.G. Bowie, L. Unterholzner, Viral evasion and subversion of pattern-recognition receptor signalling, Nat Rev Immunol 8 (2008) 911-922.
[35]B. Opitz, A. Rejaibi, B. Dauber, J. Eckhard, M. Vinzing, B. Schmeck, S. Hippenstiel, N. Suttorp, T. Wolff, IFNbeta induction by influenza A virus is mediated by RIG-I which is regulated by the viral NS1 protein, Cell Microbiol 9 (2007) 930-938.
[36]M.U. Gack, R.A. Albrecht, T. Urano, K.S. Inn, I.C. Huang, E. Carnero, M. Farzan, S. Inoue, J.U. Jung, A. Garcia-Sastre, Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I, Cell Host Microbe 5 (2009) 439-449.
[37]Z. Guo, L.M. Chen, H. Zeng, J.A. Gomez, J. Plowden, T. Fujita, J.M. Katz, R.O. Donis, S. Sambhara, NS1 protein of influenza A virus inhibits the function of intracytoplasmic pathogen sensor, RIG-I, Am J Respir Cell Mol Biol 36 (2007) 263-269.
[38]E. Meylan, J. Curran, K. Hofmann, D. Moradpour, M. Binder, R. Bartenschlager, J. Tschopp, Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus, Nature 437 (2005) 1167-1172.
[39]X.D. Li, L. Sun, R.B. Seth, G. Pineda, Z.J. Chen, Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity, Proc Natl Acad Sci U S A 102 (2005) 17717-17722.
[40]J.C. Ferreon, A.C. Ferreon, K. Li, S.M. Lemon, Molecular determinants of TRIF proteolysis mediated by the hepatitis C virus NS3/4A protease, J Biol Chem 280 (2005) 20483-20492.
[41]C.F. Basler, A. Mikulasova, L. Martinez-Sobrido, J. Paragas, E. Muhlberger, M. Bray, H.D. Klenk, P. Palese, A. Garcia-Sastre, The Ebola virus VP35 protein inhibits activation of interferon regulatory factor 3, J Virol 77 (2003) 7945-7956.
[42]W.B. Cardenas, Y.M. Loo, M. Gale, Jr., A.L. Hartman, C.R. Kimberlin, L. Martinez-Sobrido, E.O. Saphire, C.F. Basler, Ebola virus VP35 protein binds double-stranded RNA and inhibits alpha/beta interferon production induced by RIG-I signaling, J Virol 80 (2006) 5168-5178.
[43]A.L. Hartman, B.H. Bird, J.S. Towner, Z.A. Antoniadou, S.R. Zaki, S.T. Nichol, Inhibition of IRF-3 activation by VP35 is critical for the high level of virulence of ebola virus, J Virol 82 (2008) 2699-2704.
[44]S. Wieland, R. Thimme, R.H. Purcell, F.V. Chisari, Genomic analysis of the host response to hepatitis B virus infection, Proc Natl Acad Sci U S A 101 (2004) 6669-6674.
[45]S.F. Wieland, F.V. Chisari, Stealth and cunning:hepatitis B and hepatitis C viruses, J Virol 79 (2005) 9369-9380.
[46]J. Lucifora, D. Durantel, B. Testoni,O. Hantz, M. Levrero, F. Zoulim, Control of hepatitis B virus replication by innate response of HepaRG cells, Hepatology (2009).
[47]M. Hosel, M. Quasdorff, K. Wiegmann, D. Webb, U. Zedler, M. Broxtermann, R. Tedjokusumo, K. Esser, S. Arzberger, C.J. Kirschning, A. Langenkamp, C. Falk, H. Buning, S. Rose-John, U. Protzer, Not interferon, but interleukin-6 controls early gene expression in hepatitis B virus infection, Hepatology 50 (2009) 1773-1782.
[48]J. Wu, Z. Meng, M. Jiang, R. Pei, M. Trippler, R. Broering, A. Bucchi, J.P. Sowa, U. Dittmer, D. Yang, M. Roggendorf, G. Gerken, M. Lu, J.F. Schlaak, Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells, Hepatology 49(2009)1132-1140.
[49]R.G. van der Molen, D. Sprengers, R.S. Binda, E.C. de Jong, H.G. Niesters, J.G. Kusters, J. Kwekkeboom, H.L. Janssen, Functional impairment of myeloid and plasmacytoid dendritic cells of patients with chronic hepatitis B, Hepatology 40 (2004) 738-746.
[50]M. Iannacone, G. Sitia, Z.M. Ruggeri, L.G. Guidotti, HBV pathogenesis in animal models:recent advances on the role of platelets, J Hepatol 46 (2007) 719-726.
[51]S. Preiss, A. Thompson, X. Chen, S. Rodgers, V. Markovska, P. Desmond, K. Visvanathan, K. Li, S. Locarnini, P. Revill, Characterization of the innate immune signalling pathways in hepatocyte cell lines, J Viral Hepat 15 (2008) 888-900.
[52]K. Li, Z. Chen, N. Kato, M. Gale, Jr., S.M. Lemon, Distinct poly(I-C) and virus-activated signaling pathways leading to interferon-beta production in hepatocytes, J Biol Chem 280 (2005) 16739-16747.
[53]I.N. Crispe, The liver as a lymphoid organ, Annu Rev Immunol 27 (2009) 147-163.
[54]V. Christen, F. Duong, C. Bernsmeier, D. Sun, M. Nassal, M.H. Heim, Inhibition of alpha interferon signaling by hepatitis B virus, J Virol 81 (2007) 159-165.
[55]M. Wu, Y. Xu, S. Lin, X. Zhang, L. Xiang, Z. Yuan, Hepatitis B virus polymerase inhibits the interferon-inducible MyD88 promoter by blocking nuclear translocation of Statl, J Gen Virol 88 (2007) 3260-3269.
[56]J.S. Twu, C.H. Lee, P.M. Lin, R.H. Schloemer, Hepatitis B virus suppresses expression of human beta-interferon, Proc Natl Acad Sci U S A 85 (1988) 252-256.
[57]M. Yoneyama, T. Fujita, RIG-I family RNA helicases:cytoplasmic sensor for antiviral innate immunity, Cytokine Growth Factor Rev 18 (2007) 545-551.
[58]Y. Asahina, N. Izumi, I. Hirayama, T. Tanaka, M. Sato, Y. Yasui, N. Komatsu, N. Umeda, T. Hosokawa, K. Ueda, K. Tsuchiya, H. Nakanishi, J. Itakura, M. Kurosaki, N. Enomoto, M. Tasaka, N. Sakamoto, S. Miyake, Potential relevance of cytoplasmic viral sensors and related regulators involving innate immunity in antiviral response, Gastroenterology 134 (2008) 1396-1405.
[59]M. Noguchi, S. Hirohashi, Cell lines from non-neoplastic liver and hepatocellular carcinoma tissue from a single patient, In Vitro Cell Dev Biol Anim 32 (1996) 135-137.
[60]M. Yoneyama, T. Fujita, Function of RIG-I-like receptors in antiviral innate immunity, J Biol Chem 282 (2007) 15315-15318.
[61]S.Y. Liu, D.J. Sanchez, G. Cheng, New developments in the induction and antiviral effectors of type I interferon, Curr Opin Immunol 23 (2011) 57-64.
[62]Y.J. Seo, B. Hahm, Type I interferon modulates the battle of host immune system against viruses, Adv Appl Microbiol 73 (2010) 83-101.
[63]T.L. Chau, R. Gioia, J.S. Gatot, F. Patrascu, I. Carpentier, J.P. Chapelle, L. O'Neill, R. Beyaert, J. Piette, A. Chariot, Are the IKKs and IKK-related kinases TBK1 and IKK-epsilon similarly activated?, Trends Biochem Sci 33 (2008) 171-180.
[64]M.J. Servant, B. ten Oever, C. LePage, L. Conti, S. Gessani, I. Julkunen, R. Lin, J. Hiscott, Identification of distinct signaling pathways leading to the phosphorylation of interferon regulatory factor 3, J Biol Chem 276 (2001) 355-363.
[65]K. Ozato, P. Tailor, T. Kubota, The interferon regulatory factor family in host defense:mechanism of action, J Biol Chem 282 (2007) 20065-20069.
[66]D. Soulat, T. Burckstummer, S. Westermayer, A. Goncalves, A. Bauch, A. Stefanovic, O. Hantschel, K.L. Bennett, T. Decker, G. Superti-Furga, The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response, EMBO J 27 (2008) 2135-2146.
[67]H. Wang, S. Kim, W.S. Ryu, DDX3 DEAD-Box RNA helicase inhibits hepatitis B virus reverse transcription by incorporation into nucleocapsids, J Virol 83 (2009)5815-5824.
[68]C. Wei, C. Ni, T. Song, Y. Liu, X. Yang, Z. Zheng, Y. Jia, Y. Yuan, K. Guan, Y. Xu, X. Cheng, Y. Zhang, Y. Wang, C. Wen, Q. Wu, W. Shi, H. Zhong, The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein, J Immunol 185 (2010) 1158-1168.
[69]M. Kumar, S.Y. Jung, A.J. Hodgson, C.R. Madden, J. Qin, B.L. Slagle, Hepatitis B Virus Regulatory HBx Protein Binds to Adaptor Protein IPS-1 and Inhibits the Activation of Beta Interferon, J Virol 85 (2011) 987-995.
[70]M. Schroder, M. Baran, A.G. Bowie, Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKepsilon-mediated IRF activation, EMBO J 27 (2008)2147-2157.
[71]K.C. Prins, W.B. Cardenas, C.F. Basler, Ebola virus protein VP35 impairs the function of interferon regulatory factor-activating kinases IKKepsilon and TBK-1, J Virol 83 (2009) 3069-3077.
[72]K.M. Graef, F.T. Vreede, Y.F. Lau, A.W. McCall, S.M. Carr, K. Subbarao, E. Fodor, The PB2 subunit of the influenza virus RNA polymerase affects virulence by interacting with the mitochondrial antiviral signaling protein and inhibiting expression of beta interferon, J Virol 84 (2010) 8433-8445.
[73]A. Iwai, T. Shiozaki, T. Kawai, S. Akira, Y. Kawaoka, A. Takada, H. Kida, T. Miyazaki, Influenza A virus polymerase inhibits type I interferon induction by binding to interferon beta promoter stimulator 1, J Biol Chem 285 (2010) 32064-32074.
[1]S. Akira, Pathogen recognition by innate immunity and its signaling, Proc Jpn Acad Ser B Phys Biol Sci 85 (2009) 143-156.
[2]R.B. Seth, L. Sun, Z.J. Chen, Antiviral innate immunity pathways, Cell Res 16 (2006) 141-147.
[3]L. Sun, S. Liu, Z.J. Chen, SnapShot:pathways of antiviral innate immunity, Cell 140 (2010) 436-436 e432.
[4]J.E. Durbin, A. Fernandez-Sesma, C.K. Lee, T.D. Rao, A.B. Frey, T.M. Moran, S. Vukmanovic, A. Garcia-Sastre, D.E. Levy, Type Ⅰ IFN modulates innate and specific antiviral immunity, J Immunol 164 (2000) 4220-4228.
[5]Y.J. Seo, B. Hahm, Type I interferon modulates the battle of host immune system against viruses, Adv Appl Microbiol 73 (2010) 83-101.
[6]R. Barbalat, S.E. Ewald, M.L. Mouchess, G.M. Barton, Nucleic Acid recognition by the innate immune system, Annu Rev Immunol 29 (2011) 185-214.
[7]S.Y. Liu, D.J. Sanchez, G. Cheng, New developments in the induction and antiviral effectors of type I interferon, Curr Opin Immunol 23 (2011) 57-64.
[8]A. Schmidt, S. Endres, S. Rothenfusser, Pattern recognition of viral nucleic acids by RIG-I-like helicases, J Mol Med 89 (2011) 5-12.
[9]Y.H. Chiu, J.B. Macmillan, Z.J. Chen, RNA polymerase Ⅲ detects cytosolic DNA and induces type I interferons through the RIG-I pathway, Cell 138 (2009) 576-591.
[10]M. Yoneyama, T. Fujita, RIG-I family RNA helicases:cytoplasmic sensor for antiviral innate immunity, Cytokine Growth Factor Rev 18 (2007) 545-551.
[11]J.A. Potter, R.E. Randall, G.L. Taylor, Crystal structure of human IPS-1/MAVS/VISA/Cardif caspase activation recruitment domain, BMC Struc Biol 8 (2008) 11.
[12]R.B. Seth, L. Sun, C.K. Ea, Z.J. Chen, Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3, Cell 122 (2005) 669-682.
[13]M. Baril, M.E. Racine, F. Penin, D. Lamarre, MAVS dimer is a crucial signaling component of innate immunity and the target of hepatitis C virus NS3/4A protease, J Virol 83 (2009) 1299-1311.
[14]E.D. Tang, C.Y. Wang, MAVS self-association mediates antiviral innate immune signaling, J Virol 83 (2009) 3420-3428.
[15]J.S. Gatot, R. Gioia, T.L. Chau, F. Patrascu, M. Warnier, P. Close, J.P. Chapelle, E. Muraille, K. Brown, U. Siebenlist, J. Piette, E. Dejardin, A. Chariot, Lipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKKepsilon-dependent Lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAF, J Biol Chem 282 (2007) 31131-31146.
[16]T. Zhao, L. Yang, Q. Sun, M. Arguello, D.W. Ballard, J. Hiscott, R. Lin, The NEMO adaptor bridges the nuclear factor-kappaB and interferon regulatory factor signaling pathways, Nature Immunol 8 (2007) 592-600.
[17]C.S. Friedman, M.A. O'Donnell, D. Legarda-Addison, A. Ng, W.B. Cardenas, J.S. Yount, T.M. Moran, C.F. Basler, A. Komuro, C.M. Horvath, R. Xavier, A.T. Ting, The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response, EMBO Reports 9 (2008) 930-936.
[18]S. Paz, M. Vilasco, M. Arguello, Q. Sun, J. Lacoste, T.L. Nguyen, T. Zhao, E.A. Shestakova, S. Zaari, A. Bibeau-Poirier, M.J. Servant, R. Lin, E.F. Meurs, J. Hiscott, Ubiquitin-regulated recruitment of IkappaB kinase epsilon to the MAVS interferon signaling adapter, Mol Cell Biol 29 (2009) 3401-3412.
[19]K. Parvatiyar, G.N. Barber, E.W. Harhaj, TAX1BP1 and A20 inhibit antiviral signaling by targeting TBK1-IKKi kinases, J Biol Chem 285 (2010) 14999-15009.
[20]W. Zeng, M. Xu, S. Liu, L. Sun, Z.J. Chen, Key role of Ubc5 and lysine-63 polyubiquitination in viral activation of IRF3, Mol Cell 36 (2009) 315-325.
[21]C. Castanier, D. Garcin, A. Vazquez, D. Arnoult, Mitochondrial dynamics regulate the RIG-I-like receptor antiviral pathway, EMBO Reports 11 (2010) 133-138.
[22]H. Oshiumi, K. Sakai, M. Matsumoto, T. Seya, DEAD/H BOX 3 (DDX3) helicase binds the RIG-I adaptor IPS-1 to up-regulate IFN-beta-inducing potential, Eur J Immunol 40 (2010) 940-948.
[23]J. Trepel, M. Mollapour, G. Giaccone, L. Neckers, Targeting the dynamic HSP90 complex in cancer, Nat Rev Cancer 10 (2010) 537-549.
[24]S.J. Felts, B.A. Owen, P. Nguyen, J. Trepel, D.B. Donner, D.O. Toft, The hsp90-related protein TRAP1 is a mitochondrial protein with distinct functional properties, J Biol Chem 275 (2000) 3305-3312.
[25]M. Taipale, D.F. Jarosz, S. Lindquist, HSP90 at the hub of protein homeostasis: emerging mechanistic insights, Nat Rev Mol Cell Biol 11 (2010) 515-528.
[26]K. Yang, H. Shi, R. Qi, S. Sun, Y. Tang, B. Zhang, C. Wang, Hsp90 regulates activation of interferon regulatory factor 3 and TBK-1 stabilization in Sendai virus-infected cells, Mol Biol Cell 17 (2006) 1461-1471.
[27]T. Matsumiya, T. Imaizumi, H. Yoshida, K. Satoh, M.K. Topham, D.M. Stafforini, The levels of retinoic acid-inducible gene I are regulated by heat shock protein 90-alpha, J Immunol 182 (2009) 2717-2725.
[28]X.Y. Liu, B. Wei, H.X. Shi, Y.F. Shan, C. Wang, Tom70 mediates activation of interferon regulatory factor 3 on mitochondria, Cell Res 20 (2010) 994-1011.
[29]J.W. Pridgeon, J.A. Olzmann, L.S. Chin, L. Li, PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1, PLoS Biol 5 (2007) e172.
[30]M. Landriscina, G. Laudiero, F. Maddalena, M.R. Amoroso, A. Piscazzi, F. Cozzolino, M. Monti, C. Garbi, A. Fersini, P. Pucci, F. Esposito, Mitochondrial chaperone Trapl and the calcium binding protein Sorcin interact and protect cells against apoptosis induced by antiblastic agents, Cancer Res 70 (2010) 6577-6586.
[31]X.D. Li, L. Sun, R.B. Seth, G. Pineda, Z.J. Chen, Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity, Proc Natl Acad Sci U S A 102 (2005) 17717-17722.
[32]K.M. Graef, F.T. Vreede, Y.F. Lau, A.W. McCall, S.M. Carr, K. Subbarao, E. Fodor, The PB2 subunit of the influenza virus RNA polymerase affects virulence by interacting with the mitochondrial antiviral signaling protein and inhibiting expression of beta interferon, J Virol 84 (2010) 8433-8445.
[33]M. Kumar, S.Y. Jung, A.J. Hodgson, C.R. Madden, J. Qin, B.L. Slagle, Hepatitis B Virus Regulatory HBx Protein Binds to Adaptor Protein IPS-1 and Inhibits the Activation of Beta Interferon, J Virol 85 (2011) 987-995.
[34]C. Wei, C. Ni, T. Song, Y. Liu, X. Yang, Z. Zheng, Y. Jia, Y. Yuan, K. Guan, Y. Xu, X. Cheng, Y. Zhang, Y. Wang, C. Wen, Q. Wu, W. Shi, H. Zhong, The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein, J Immunol 185 (2010) 1158-1168.
[35]S. Yu, J. Chen, M. Wu, H. Chen, N. Kato, Z. Yuan, Hepatitis B virus polymerase inhibits RIG-I- and Toll-like receptor 3-mediated beta interferon induction in human hepatocytes through interference with interferon regulatory factor 3 activation and dampening of the interaction between TBK1/IKKepsilon and DDX3, J Gen Virol 91 (2010) 2080-2090.
[36]S. Sharma, B.R. tenOever, N. Grandvaux, G.P. Zhou, R. Lin, J. Hiscott, Triggering the interferon antiviral response through an IKK-related pathway, Science 300 (2003) 1148-1151.
[37]Z. Lu, T. Hunter, Degradation of activated protein kinases by ubiquitination, Annu Rev Biochem 78 (2009) 435-475.
[38]N. Kishore, Q.K. Huynh, S. Mathialagan, T. Hall, S. Rouw, D. Creely, G. Lange, J. Caroll, B. Reitz, A. Donnelly, H. Boddupalli, R.G. Combs, K. Kretzmer, C.S. Tripp, IKK-i and TBK-1 are enzymatically distinct from the homologous enzyme IKK-2: comparative analysis of recombinant human IKK-i, TBK-1, and IKK-2, J Biol Chem 277 (2002) 13840-13847.
[39]J. Beck, M. Nassal, Efficient Hsp90-independent in vitro activation by Hsc70 and Hsp40 of duck hepatitis B virus reverse transcriptase, an assumed Hsp90 client protein, J Biol Chem 278 (2003) 36128-36138.
[40]K. Liu, L. Qian, J. Wang, W. Li, X. Deng, X. Chen, W. Sun, H. Wei, X. Qian, Y. Jiang, F. He, Two-dimensional blue native/SDS-PAGE analysis reveals heat shock protein chaperone machinery involved in hepatitis B virus production in HepG2.2.15 cells, Mol Cell Proteomics 8 (2009) 495-505.
[41]S.M. McWhirter, B.R. Tenoever, T. Maniatis, Connecting mitochondria and innate immunity, Cell 122 (2005) 645-647.
[42]F. Cao, J.E. Tavis, Detection and characterization of cytoplasmic hepatitis B virus reverse transcriptase, J Gen Virol 85 (2004) 3353-3360.
[43]Y. Minami, Y. Kimura, H. Kawasaki, K. Suzuki, I. Yahara, The carboxy-terminal region of mammalian HSP90 is required for its dimerization and function in vivo, Mol Cell Biol 14 (1994) 1459-1464.
[44]N. Wayne, D.N. Bolon, Dimerization of Hsp90 is required for in vivo function. Design and analysis of monomers and dimers, J Biol Chem 282 (2007) 35386-35395.
[45]F. Zoulim, New insight on hepatitis B virus persistence from the study of intrahepatic viral cccDNA, J Hepatol 42 (2005) 302-308.
[46]S. Benhenda, D. Cougot, M.A. Buendia, C. Neuveut, Hepatitis B virus X protein molecular functions and its role in virus life cycle and pathogenesis, Adv Cancer Res 103 (2009) 75-109.
[47]S.F. Wieland, F.V. Chisari, Stealth and cunning:hepatitis B and hepatitis C viruses, J Virol 79 (2005) 9369-9380.
[48]J. Wu, Z. Meng, M. Jiang, R. Pei, M. Trippler, R. Broering, A. Bucchi, J.P. Sowa, U. Dittmer, D. Yang, M. Roggendorf, G. Gerken, M. Lu, J.F. Schlaak, Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells, Hepatology 49 (2009) 1132-1140.
[49]H. Wang, W.S. Ryu, Hepatitis B virus polymerase blocks pattern recognition receptor signaling via interaction with DDX3:implications for immune evasion, PLoS Pathog 6 (2010) e1000986.
[1]S. Akira, Pathogen recognition by innate immunity and its signaling, Proc Jpn Acad Ser B Phys Biol Sci 85 (2009) 143-156.
[2]S. Akira, S. Uematsu,O. Takeuchi, Pathogen recognition and innate immunity, Cell 124 (2006) 783-801.
[3]S.M. McWhirter, B.R. Tenoever, T. Maniatis, Connecting mitochondria and innate immunity, Cell 122 (2005) 645-647.
[4]E. Dixit, S. Boulant, Y. Zhang, A.S. Lee, C. Odendall, B. Shum, N. Hacohen, Z.J. Chen, S.P. Whelan, M. Fransen, M.L. Nibert, G. Superti-Furga, J.C. Kagan, Peroxisomes are signaling platforms for antiviral innate immunity, Cell 141 (2010)668-681.
[5]T. Kawai, K. Takahashi, S. Sato, C. Coban, H. Kumar, H. Kato, K.J. Ishii, O. Takeuchi, S. Akira, IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction, Nature Immunol 6 (2005) 981-988.
[6]E. Meylan, J. Curran, K. Hofmann, D. Moradpour, M. Binder, R. Bartenschlager, J. Tschopp, Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus, Nature 437 (2005) 1167-1172.
[7]R.B. Seth, L. Sun, C.K. Ea, Z.J. Chen, Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3, Cell 122 (2005) 669-682.
[8]L.G. Xu, Y.Y. Wang, K.J. Han, L.Y. Li, Z. Zhai, H.B. Shu, VISA is an adapter protein required for virus-triggered IFN-beta signaling, Mol Cell 19 (2005) 727-740.
[9]E.D. Tang, C.Y. Wang, MAVS self-association mediates antiviral innate immune signaling, J Virol 83 (2009) 3420-3428.
[10]M. Baril, M.E. Racine, F. Penin, D. Lamarre, MAVS dimer is a crucial signaling component of innate immunity and the target of hepatitis C virus NS3/4A protease, J Virol 83 (2009) 1299-1311.
[11]C. Wei, C. Ni, T. Song, Y. Liu, X. Yang, Z. Zheng, Y. Jia, Y. Yuan, K. Guan, Y. Xu, X. Cheng, Y. Zhang, Y. Wang, C. Wen, Q. Wu, W. Shi, H. Zhong, The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein, J Immunol 185 (2010) 1158-1168.
[12]S. Paz, M. Vilasco, M. Arguello, Q. Sun, J. Lacoste, T.L. Nguyen, T. Zhao, E.A. Shestakova, S. Zaari, A. Bibeau-Poirier, M.J. Servant, R. Lin, E.F. Meurs, J. Hiscott, Ubiquitin-regulated recruitment of IkappaB kinase epsilon to the MAVS interferon signaling adapter, Mol Cell Biol 29 (2009) 3401-3412.
[13]K. Onoguchi, K. Onomoto, S. Takamatsu, M. Jogi, A. Takemura, S. Morimoto, I. Julkunen, H. Namiki, M. Yoneyama, T. Fujita, Virus-infection or 5'ppp-RNA activates antiviral signal through redistribution of IPS-1 mediated by MFN1, PLoS pathogens 6 (2010) e1001012.
[14]C. Castanier, D. Garcin, A. Vazquez, D. Arnoult, Mitochondrial dynamics regulate the RIG-I-like receptor antiviral pathway, EMBO Reports 11 (2010) 133-138.
[15]M. Schroder, Viruses and the human DEAD-box helicase DDX3:inhibition or exploitation?, Biochem Soc Trans 39 (2011) 679-683.
[16]M. Schroder, M. Baran, A.G. Bowie, Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKepsilon-mediated IRF activation, EMBO J 27 (2008) 2147-2157.
[17]D. Soulat, T. Burckstummer, S. Westermayer, A. Goncalves, A. Bauch, A. Stefanovic, O. Hantschel, K.L. Bennett, T. Decker, G. Superti-Furga, The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response, EMBO J 27 (2008) 2135-2146.
[18]H. Oshiumi, K. Sakai, M. Matsumoto, T. Seya, DEAD/H BOX 3 (DDX3) helicase binds the RIG-I adaptor IPS-1 to up-regulate IFN-beta-inducing potential, Eur J Immunol 40 (2010) 940-948.
[19]T. Song, C. Wei, Z. Zheng, Y. Xu, X. Cheng, Y. Yuan, K. Guan, Y. Zhang, Q. Ma, W. Shi, H. Zhong, c-Abl tyrosine kinase interacts with MAVS and regulates innate immune response, FEBS letters 584 (2010) 33-38.
[20]Y.Y. Wang, L.J. Liu, B. Zhong, T.T. Liu, Y. Li, Y. Yang, Y. Ran, S. Li, P. Tien, H.B. Shu, WDR5 is essential for assembly of the VISA-associated signaling complex and virus-triggered IRF3 and NF-kappaB activation, Proc Natl Acad Sci US A 107 (2010) 815-820.
[21]C.B. Moore, D.T. Bergstralh, J.A. Duncan, Y. Lei, T.E. Morrison, A.G. Zimmermann, M.A. Accavitti-Loper, V.J. Madden, L. Sun, Z. Ye, J.D. Lich, M.T. Heise, Z. Chen, J.P. Ting, NLRX1 is a regulator of mitochondrial antiviral immunity, Nature 451 (2008) 573-577.
[22]F. You, H. Sun, X. Zhou, W. Sun, S. Liang, Z. Zhai, Z. Jiang, PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4, Nature Immunol 10 (2009) 1300-1308.
[23]D. Vitour, S. Dabo, M. Ahmadi Pour, M. Vilasco, P.O. Vidalain, Y. Jacob, M. Mezel-Lemoine, S. Paz, M. Arguello, R. Lin, F. Tangy, J. Hiscott, E.F. Meurs, Polo-like kinase 1 (PLK1) regulates interferon (IFN) induction by MAVS, J Biol Chem 284 (2009) 21797-21809.
[24]K. Yasukawa, H. Oshiumi, M. Takeda, N. Ishihara, Y. Yanagi, T. Seya, S. Kawabata, T. Koshiba, Mitofusin 2 inhibits mitochondrial antiviral signaling, Science Signaling 2 (2009) ra47.
[25]X.D. Li, L. Sun, R.B. Seth, G. Pineda, Z.J. Chen, Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity, Proc Natl Acad Sci U S A 102 (2005) 17717-17722.
[26]Y. Yang, Y. Liang, L. Qu, Z. Chen, M. Yi, K. Li, S.M. Lemon, Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursor, Proc Natl Acad Sci USA104 (2007) 7253-7258.
[27]M. Rebsamen, E. Meylan, J. Curran, J. Tschopp, The antiviral adaptor proteins Cardif and Trif are processed and inactivated by caspases, Cell Death Differentiation 15 (2008) 1804-1811.
[28]I. Scott, K.L. Norris, The mitochondrial antiviral signaling protein, MAVS, is cleaved during apoptosis, Biochem Biophys Res Commun 375 (2008) 101-106.
[29]A. Iwai, T. Shiozaki, T. Kawai, S. Akira, Y. Kawaoka, A. Takada, H. Kida, T. Miyazaki, Influenza A virus polymerase inhibits type I interferon induction by binding to interferon beta promoter stimulator 1, J Biol Chem 285 (2010) 32064-32074.
[30]K.M. Graef, F.T. Vreede, Y.F. Lau, A.W. McCall, S.M. Carr, K. Subbarao, E. Fodor, The PB2 subunit of the influenza virus RNA polymerase affects virulence by interacting with the mitochondrial antiviral signaling protein and inhibiting expression of beta interferon, J Virol 84 (2010) 8433-8445.
[31]M. Kumar, S.Y. Jung, A.J. Hodgson, C.R. Madden, J. Qin, B.L. Slagle, Hepatitis B Virus Regulatory HBx Protein Binds to Adaptor Protein IPS-1 and Inhibits the Activation of Beta Interferon, J Virol 85 (2011) 987-995.
[2]S.A. Gonzalez, E.B. Keeffe, Chronic viral hepatitis:epidemiology, molecular biology, and antiviral therapy, Front Biosci 16 (2011) 225-250.
[3]G. Fattovich, F. Bortolotti, F. Donato, Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors, J Hepatol 48 (2008) 335-352.
[4]P. Bonanni, G. Pesavento, S. Boccalini, A. Bechini, Perspectives of public health: present and foreseen impact of vaccination on the epidemiology of hepatitis B, J Hepatol 39 Suppl 1 (2003) S224-229.
[5]F. Zoulim, Hepatitis B virus resistance to antivirals:clinical implications and management, J Hepatol 39 Suppl 1 (2003) S133-138.
[6]M. van Zonneveld, P. Honkoop, B.E. Hansen, H.G. Niesters, S. Darwish Murad, R.A. de Man, S.W. Schalm, H.L. Janssen, Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B, Hepatology 39 (2004) 804-810.
[7]C. Seeger, W.S. Mason, Hepatitis B virus biology, Microbiol Mol Biol Rev 64 (2000)51-68.
[8]F. Zoulim, New insight on hepatitis B virus persistence from the study of intrahepatic viral cccDNA, J Hepatol 42 (2005) 302-308.
[9]X. Lu, T. Block, Study of the early steps of the Hepatitis B Virus life cycle, Int J Med Sci 1(2004) 21-33.
[10]C.M. Bremer, I. Sominskaya, D. Skrastina, P. Pumpens, A.A. El Wahed, U. Beutling, R. Frank, H.J. Fritz, G. Hunsmann, W.H. Gerlich, D. Glebe, N-terminal myristoylation-dependent masking of neutralizing epitopes in the preS1 attachment site of hepatitis B virus, J Hepatol (2010).
[11]D. Glebe, S. Urban, E.V. Knoop, N. Cag, P. Krass, S. Grun, A. Bulavaite, K. Sasnauskas, W.H. Gerlich, Mapping of the hepatitis B virus attachment site by use of infection-inhibiting preS1 lipopeptides and tupaia hepatocytes, Gastroenterology 129 (2005) 234-245.
[12]S. Benhenda, D. Cougot, M.A. Buendia, C. Neuveut, Hepatitis B virus X protein molecular functions and its role in virus life cycle and pathogenesis, Adv Cancer Res 103 (2009) 75-109.
[13]S.L. McClain, A.J. Clippinger, R. Lizzano, M.J. Bouchard, Hepatitis B virus replication is associated with an HBx-dependent mitochondrion-regulated increase in cytosolic calcium levels, J Virol 81 (2007) 12061-12065.
[14]J. Lucifora, S. Arzberger, D. Durantel, L. Belloni, M. Strubin, M. Levrero, F. Zoulim, O. Hantz, U. Protzer, Hepatitis B Virus X protein is essential to initiate and maintain virus replication after infection, J Hepatol (2011).
[15]S. Akira, S. Uematsu, O. Takeuchi, Pathogen recognition and innate immunity, Cell 124 (2006) 783-801.
[16]L.R. Sabin, S.L. Hanna, S. Cherry, Innate antiviral immunity in Drosophila, Curr Opin Immunol 22 (2010) 4-9.
[17]D.M. Andrews, M.J. Estcourt, C.E. Andoniou, M.E. Wikstrom, A. Khong, V. Voigt, P. Fleming, H. Tabarias, G.R. Hill, R.G. van der Most, A.A. Scalzo, M.J. Smyth, M.A. Degli-Esposti, Innate immunity defines the capacity of antiviral T cells to limit persistent infection, J Exp Med 207 (2010) 1333-1343.
[18]W.L. Chang, P.A. Barry, Attenuation of innate immunity by cytomegalovirus IL-10 establishes a long-term deficit of adaptive antiviral immunity, Proc Natl Acad Sci U S A 107 (2010) 22647-22652.
[19]J.E. Durbin, A. Fernandez-Sesma, C.K. Lee, T.D. Rao, A.B. Frey, T.M. Moran, S. Vukmanovic, A. Garcia-Sastre, D.E. Levy, Type ⅠIFN modulates innate and specific antiviral immunity, J Immunol 164 (2000) 4220-4228.
[20]G. Trinchieri, Type I interferon:friend or foe?, J Exp Med 207 (2010) 2053-2063.
[21]S. Akira, Pathogen recognition by innate immunity and its signaling, Proc Jpn Acad Phys SerB Biol Sci 85 (2009) 143-156.
[22]L.A. O'Neill, A.G. Bowie, Sensing and signaling in antiviral innate immunity, Curr Biol 20 (2010) R328-333.
[23]A. Sabbah, T.H. Chang, R. Harnack, V. Frohlich, K. Tominaga, P.H. Dube, Y. Xiang, S. Bose, Activation of innate immune antiviral responses by Nod2, Nature Immunol 10 (2009) 1073-1080.
[24]V.A. Rathinam, Z. Jiang, S.N. Waggoner, S. Sharma, L.E. Cole, L. Waggoner, S.K. Vanaja, B.G. Monks, S. Ganesan, E. Latz, V. Hornung, S.N. Vogel, E. Szomolanyi-Tsuda, K.A. Fitzgerald, The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses, Nature Immunol 11 (2010)395-402.
[25]H. Kato, S. Sato, M. Yoneyama, M. Yamamoto, S. Uematsu, K. Matsui, T. Tsujimura, K. Takeda, T. Fujita, O. Takeuchi, S. Akira, Cell type-specific involvement of RIG-I in antiviral response, Immunity 23 (2005) 19-28.
[26]K. Honda, T. Taniguchi, IRFs:master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors, Nature Rev Immunol 6 (2006) 644-658.
[27]M.J. Servant, N. Grandvaux, J. Hiscott, Multiple signaling pathways leading to the activation of interferon regulatory factor 3, Biochem Pharmacol 64 (2002) 985-992.
[28]W. Zeng, M. Xu, S. Liu, L. Sun, Z.J. Chen, Key role of Ubc5 and lysine-63 polyubiquitination in viral activation of IRF3, Mol Cell 36 (2009) 315-325.
[29]L. Sun, S. Liu, Z.J. Chen, SnapShot:pathways of antiviral innate immunity, Cell 140 (2010) 436-436 e432.
[30]T. Taniguchi, A. Takaoka, The interferon-alpha/beta system in antiviral responses: a multimodal machinery of gene regulation by the IRF family of transcription factors, Curr Opin Immunol 14 (2002) 111-116.
[31]A.K. Erickson, M. Gale, Jr., Regulation of interferon production and innate antiviral immunity through translational control of IRF-7, Cell Res 18 (2008) 433-435.
[32]C.R. Roy, E.S. Mocarski, Pathogen subversion of cell-intrinsic innate immunity, Nat Immunol 8 (2007) 1179-1187.
[33]L.M. Hook, H.M. Friedman, Subversion of innate and adaptive immunity: immune evasion from antibody and complement, in:A. Arvin, G. Campadelli-Fiume, E. Mocarski, P.S. Moore, B. Roizman, R. Whitley, K. Yamanishi (Eds.), Human Herpesviruses:Biology, Therapy, and Immunoprophylaxis, Cambridge,2007.
[34]A.G. Bowie, L. Unterholzner, Viral evasion and subversion of pattern-recognition receptor signalling, Nat Rev Immunol 8 (2008) 911-922.
[35]B. Opitz, A. Rejaibi, B. Dauber, J. Eckhard, M. Vinzing, B. Schmeck, S. Hippenstiel, N. Suttorp, T. Wolff, IFNbeta induction by influenza A virus is mediated by RIG-I which is regulated by the viral NS1 protein, Cell Microbiol 9 (2007) 930-938.
[36]M.U. Gack, R.A. Albrecht, T. Urano, K.S. Inn, I.C. Huang, E. Carnero, M. Farzan, S. Inoue, J.U. Jung, A. Garcia-Sastre, Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I, Cell Host Microbe 5 (2009) 439-449.
[37]Z. Guo, L.M. Chen, H. Zeng, J.A. Gomez, J. Plowden, T. Fujita, J.M. Katz, R.O. Donis, S. Sambhara, NS1 protein of influenza A virus inhibits the function of intracytoplasmic pathogen sensor, RIG-I, Am J Respir Cell Mol Biol 36 (2007) 263-269.
[38]E. Meylan, J. Curran, K. Hofmann, D. Moradpour, M. Binder, R. Bartenschlager, J. Tschopp, Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus, Nature 437 (2005) 1167-1172.
[39]X.D. Li, L. Sun, R.B. Seth, G. Pineda, Z.J. Chen, Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity, Proc Natl Acad Sci U S A 102 (2005) 17717-17722.
[40]J.C. Ferreon, A.C. Ferreon, K. Li, S.M. Lemon, Molecular determinants of TRIF proteolysis mediated by the hepatitis C virus NS3/4A protease, J Biol Chem 280 (2005) 20483-20492.
[41]C.F. Basler, A. Mikulasova, L. Martinez-Sobrido, J. Paragas, E. Muhlberger, M. Bray, H.D. Klenk, P. Palese, A. Garcia-Sastre, The Ebola virus VP35 protein inhibits activation of interferon regulatory factor 3, J Virol 77 (2003) 7945-7956.
[42]W.B. Cardenas, Y.M. Loo, M. Gale, Jr., A.L. Hartman, C.R. Kimberlin, L. Martinez-Sobrido, E.O. Saphire, C.F. Basler, Ebola virus VP35 protein binds double-stranded RNA and inhibits alpha/beta interferon production induced by RIG-I signaling, J Virol 80 (2006) 5168-5178.
[43]A.L. Hartman, B.H. Bird, J.S. Towner, Z.A. Antoniadou, S.R. Zaki, S.T. Nichol, Inhibition of IRF-3 activation by VP35 is critical for the high level of virulence of ebola virus, J Virol 82 (2008) 2699-2704.
[44]S. Wieland, R. Thimme, R.H. Purcell, F.V. Chisari, Genomic analysis of the host response to hepatitis B virus infection, Proc Natl Acad Sci U S A 101 (2004) 6669-6674.
[45]S.F. Wieland, F.V. Chisari, Stealth and cunning:hepatitis B and hepatitis C viruses, J Virol 79 (2005) 9369-9380.
[46]J. Lucifora, D. Durantel, B. Testoni,O. Hantz, M. Levrero, F. Zoulim, Control of hepatitis B virus replication by innate response of HepaRG cells, Hepatology (2009).
[47]M. Hosel, M. Quasdorff, K. Wiegmann, D. Webb, U. Zedler, M. Broxtermann, R. Tedjokusumo, K. Esser, S. Arzberger, C.J. Kirschning, A. Langenkamp, C. Falk, H. Buning, S. Rose-John, U. Protzer, Not interferon, but interleukin-6 controls early gene expression in hepatitis B virus infection, Hepatology 50 (2009) 1773-1782.
[48]J. Wu, Z. Meng, M. Jiang, R. Pei, M. Trippler, R. Broering, A. Bucchi, J.P. Sowa, U. Dittmer, D. Yang, M. Roggendorf, G. Gerken, M. Lu, J.F. Schlaak, Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells, Hepatology 49(2009)1132-1140.
[49]R.G. van der Molen, D. Sprengers, R.S. Binda, E.C. de Jong, H.G. Niesters, J.G. Kusters, J. Kwekkeboom, H.L. Janssen, Functional impairment of myeloid and plasmacytoid dendritic cells of patients with chronic hepatitis B, Hepatology 40 (2004) 738-746.
[50]M. Iannacone, G. Sitia, Z.M. Ruggeri, L.G. Guidotti, HBV pathogenesis in animal models:recent advances on the role of platelets, J Hepatol 46 (2007) 719-726.
[51]S. Preiss, A. Thompson, X. Chen, S. Rodgers, V. Markovska, P. Desmond, K. Visvanathan, K. Li, S. Locarnini, P. Revill, Characterization of the innate immune signalling pathways in hepatocyte cell lines, J Viral Hepat 15 (2008) 888-900.
[52]K. Li, Z. Chen, N. Kato, M. Gale, Jr., S.M. Lemon, Distinct poly(I-C) and virus-activated signaling pathways leading to interferon-beta production in hepatocytes, J Biol Chem 280 (2005) 16739-16747.
[53]I.N. Crispe, The liver as a lymphoid organ, Annu Rev Immunol 27 (2009) 147-163.
[54]V. Christen, F. Duong, C. Bernsmeier, D. Sun, M. Nassal, M.H. Heim, Inhibition of alpha interferon signaling by hepatitis B virus, J Virol 81 (2007) 159-165.
[55]M. Wu, Y. Xu, S. Lin, X. Zhang, L. Xiang, Z. Yuan, Hepatitis B virus polymerase inhibits the interferon-inducible MyD88 promoter by blocking nuclear translocation of Statl, J Gen Virol 88 (2007) 3260-3269.
[56]J.S. Twu, C.H. Lee, P.M. Lin, R.H. Schloemer, Hepatitis B virus suppresses expression of human beta-interferon, Proc Natl Acad Sci U S A 85 (1988) 252-256.
[57]M. Yoneyama, T. Fujita, RIG-I family RNA helicases:cytoplasmic sensor for antiviral innate immunity, Cytokine Growth Factor Rev 18 (2007) 545-551.
[58]Y. Asahina, N. Izumi, I. Hirayama, T. Tanaka, M. Sato, Y. Yasui, N. Komatsu, N. Umeda, T. Hosokawa, K. Ueda, K. Tsuchiya, H. Nakanishi, J. Itakura, M. Kurosaki, N. Enomoto, M. Tasaka, N. Sakamoto, S. Miyake, Potential relevance of cytoplasmic viral sensors and related regulators involving innate immunity in antiviral response, Gastroenterology 134 (2008) 1396-1405.
[59]M. Noguchi, S. Hirohashi, Cell lines from non-neoplastic liver and hepatocellular carcinoma tissue from a single patient, In Vitro Cell Dev Biol Anim 32 (1996) 135-137.
[60]M. Yoneyama, T. Fujita, Function of RIG-I-like receptors in antiviral innate immunity, J Biol Chem 282 (2007) 15315-15318.
[61]S.Y. Liu, D.J. Sanchez, G. Cheng, New developments in the induction and antiviral effectors of type I interferon, Curr Opin Immunol 23 (2011) 57-64.
[62]Y.J. Seo, B. Hahm, Type I interferon modulates the battle of host immune system against viruses, Adv Appl Microbiol 73 (2010) 83-101.
[63]T.L. Chau, R. Gioia, J.S. Gatot, F. Patrascu, I. Carpentier, J.P. Chapelle, L. O'Neill, R. Beyaert, J. Piette, A. Chariot, Are the IKKs and IKK-related kinases TBK1 and IKK-epsilon similarly activated?, Trends Biochem Sci 33 (2008) 171-180.
[64]M.J. Servant, B. ten Oever, C. LePage, L. Conti, S. Gessani, I. Julkunen, R. Lin, J. Hiscott, Identification of distinct signaling pathways leading to the phosphorylation of interferon regulatory factor 3, J Biol Chem 276 (2001) 355-363.
[65]K. Ozato, P. Tailor, T. Kubota, The interferon regulatory factor family in host defense:mechanism of action, J Biol Chem 282 (2007) 20065-20069.
[66]D. Soulat, T. Burckstummer, S. Westermayer, A. Goncalves, A. Bauch, A. Stefanovic, O. Hantschel, K.L. Bennett, T. Decker, G. Superti-Furga, The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response, EMBO J 27 (2008) 2135-2146.
[67]H. Wang, S. Kim, W.S. Ryu, DDX3 DEAD-Box RNA helicase inhibits hepatitis B virus reverse transcription by incorporation into nucleocapsids, J Virol 83 (2009)5815-5824.
[68]C. Wei, C. Ni, T. Song, Y. Liu, X. Yang, Z. Zheng, Y. Jia, Y. Yuan, K. Guan, Y. Xu, X. Cheng, Y. Zhang, Y. Wang, C. Wen, Q. Wu, W. Shi, H. Zhong, The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein, J Immunol 185 (2010) 1158-1168.
[69]M. Kumar, S.Y. Jung, A.J. Hodgson, C.R. Madden, J. Qin, B.L. Slagle, Hepatitis B Virus Regulatory HBx Protein Binds to Adaptor Protein IPS-1 and Inhibits the Activation of Beta Interferon, J Virol 85 (2011) 987-995.
[70]M. Schroder, M. Baran, A.G. Bowie, Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKepsilon-mediated IRF activation, EMBO J 27 (2008)2147-2157.
[71]K.C. Prins, W.B. Cardenas, C.F. Basler, Ebola virus protein VP35 impairs the function of interferon regulatory factor-activating kinases IKKepsilon and TBK-1, J Virol 83 (2009) 3069-3077.
[72]K.M. Graef, F.T. Vreede, Y.F. Lau, A.W. McCall, S.M. Carr, K. Subbarao, E. Fodor, The PB2 subunit of the influenza virus RNA polymerase affects virulence by interacting with the mitochondrial antiviral signaling protein and inhibiting expression of beta interferon, J Virol 84 (2010) 8433-8445.
[73]A. Iwai, T. Shiozaki, T. Kawai, S. Akira, Y. Kawaoka, A. Takada, H. Kida, T. Miyazaki, Influenza A virus polymerase inhibits type I interferon induction by binding to interferon beta promoter stimulator 1, J Biol Chem 285 (2010) 32064-32074.
[1]S. Akira, Pathogen recognition by innate immunity and its signaling, Proc Jpn Acad Ser B Phys Biol Sci 85 (2009) 143-156.
[2]R.B. Seth, L. Sun, Z.J. Chen, Antiviral innate immunity pathways, Cell Res 16 (2006) 141-147.
[3]L. Sun, S. Liu, Z.J. Chen, SnapShot:pathways of antiviral innate immunity, Cell 140 (2010) 436-436 e432.
[4]J.E. Durbin, A. Fernandez-Sesma, C.K. Lee, T.D. Rao, A.B. Frey, T.M. Moran, S. Vukmanovic, A. Garcia-Sastre, D.E. Levy, Type Ⅰ IFN modulates innate and specific antiviral immunity, J Immunol 164 (2000) 4220-4228.
[5]Y.J. Seo, B. Hahm, Type I interferon modulates the battle of host immune system against viruses, Adv Appl Microbiol 73 (2010) 83-101.
[6]R. Barbalat, S.E. Ewald, M.L. Mouchess, G.M. Barton, Nucleic Acid recognition by the innate immune system, Annu Rev Immunol 29 (2011) 185-214.
[7]S.Y. Liu, D.J. Sanchez, G. Cheng, New developments in the induction and antiviral effectors of type I interferon, Curr Opin Immunol 23 (2011) 57-64.
[8]A. Schmidt, S. Endres, S. Rothenfusser, Pattern recognition of viral nucleic acids by RIG-I-like helicases, J Mol Med 89 (2011) 5-12.
[9]Y.H. Chiu, J.B. Macmillan, Z.J. Chen, RNA polymerase Ⅲ detects cytosolic DNA and induces type I interferons through the RIG-I pathway, Cell 138 (2009) 576-591.
[10]M. Yoneyama, T. Fujita, RIG-I family RNA helicases:cytoplasmic sensor for antiviral innate immunity, Cytokine Growth Factor Rev 18 (2007) 545-551.
[11]J.A. Potter, R.E. Randall, G.L. Taylor, Crystal structure of human IPS-1/MAVS/VISA/Cardif caspase activation recruitment domain, BMC Struc Biol 8 (2008) 11.
[12]R.B. Seth, L. Sun, C.K. Ea, Z.J. Chen, Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3, Cell 122 (2005) 669-682.
[13]M. Baril, M.E. Racine, F. Penin, D. Lamarre, MAVS dimer is a crucial signaling component of innate immunity and the target of hepatitis C virus NS3/4A protease, J Virol 83 (2009) 1299-1311.
[14]E.D. Tang, C.Y. Wang, MAVS self-association mediates antiviral innate immune signaling, J Virol 83 (2009) 3420-3428.
[15]J.S. Gatot, R. Gioia, T.L. Chau, F. Patrascu, M. Warnier, P. Close, J.P. Chapelle, E. Muraille, K. Brown, U. Siebenlist, J. Piette, E. Dejardin, A. Chariot, Lipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKKepsilon-dependent Lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAF, J Biol Chem 282 (2007) 31131-31146.
[16]T. Zhao, L. Yang, Q. Sun, M. Arguello, D.W. Ballard, J. Hiscott, R. Lin, The NEMO adaptor bridges the nuclear factor-kappaB and interferon regulatory factor signaling pathways, Nature Immunol 8 (2007) 592-600.
[17]C.S. Friedman, M.A. O'Donnell, D. Legarda-Addison, A. Ng, W.B. Cardenas, J.S. Yount, T.M. Moran, C.F. Basler, A. Komuro, C.M. Horvath, R. Xavier, A.T. Ting, The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response, EMBO Reports 9 (2008) 930-936.
[18]S. Paz, M. Vilasco, M. Arguello, Q. Sun, J. Lacoste, T.L. Nguyen, T. Zhao, E.A. Shestakova, S. Zaari, A. Bibeau-Poirier, M.J. Servant, R. Lin, E.F. Meurs, J. Hiscott, Ubiquitin-regulated recruitment of IkappaB kinase epsilon to the MAVS interferon signaling adapter, Mol Cell Biol 29 (2009) 3401-3412.
[19]K. Parvatiyar, G.N. Barber, E.W. Harhaj, TAX1BP1 and A20 inhibit antiviral signaling by targeting TBK1-IKKi kinases, J Biol Chem 285 (2010) 14999-15009.
[20]W. Zeng, M. Xu, S. Liu, L. Sun, Z.J. Chen, Key role of Ubc5 and lysine-63 polyubiquitination in viral activation of IRF3, Mol Cell 36 (2009) 315-325.
[21]C. Castanier, D. Garcin, A. Vazquez, D. Arnoult, Mitochondrial dynamics regulate the RIG-I-like receptor antiviral pathway, EMBO Reports 11 (2010) 133-138.
[22]H. Oshiumi, K. Sakai, M. Matsumoto, T. Seya, DEAD/H BOX 3 (DDX3) helicase binds the RIG-I adaptor IPS-1 to up-regulate IFN-beta-inducing potential, Eur J Immunol 40 (2010) 940-948.
[23]J. Trepel, M. Mollapour, G. Giaccone, L. Neckers, Targeting the dynamic HSP90 complex in cancer, Nat Rev Cancer 10 (2010) 537-549.
[24]S.J. Felts, B.A. Owen, P. Nguyen, J. Trepel, D.B. Donner, D.O. Toft, The hsp90-related protein TRAP1 is a mitochondrial protein with distinct functional properties, J Biol Chem 275 (2000) 3305-3312.
[25]M. Taipale, D.F. Jarosz, S. Lindquist, HSP90 at the hub of protein homeostasis: emerging mechanistic insights, Nat Rev Mol Cell Biol 11 (2010) 515-528.
[26]K. Yang, H. Shi, R. Qi, S. Sun, Y. Tang, B. Zhang, C. Wang, Hsp90 regulates activation of interferon regulatory factor 3 and TBK-1 stabilization in Sendai virus-infected cells, Mol Biol Cell 17 (2006) 1461-1471.
[27]T. Matsumiya, T. Imaizumi, H. Yoshida, K. Satoh, M.K. Topham, D.M. Stafforini, The levels of retinoic acid-inducible gene I are regulated by heat shock protein 90-alpha, J Immunol 182 (2009) 2717-2725.
[28]X.Y. Liu, B. Wei, H.X. Shi, Y.F. Shan, C. Wang, Tom70 mediates activation of interferon regulatory factor 3 on mitochondria, Cell Res 20 (2010) 994-1011.
[29]J.W. Pridgeon, J.A. Olzmann, L.S. Chin, L. Li, PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1, PLoS Biol 5 (2007) e172.
[30]M. Landriscina, G. Laudiero, F. Maddalena, M.R. Amoroso, A. Piscazzi, F. Cozzolino, M. Monti, C. Garbi, A. Fersini, P. Pucci, F. Esposito, Mitochondrial chaperone Trapl and the calcium binding protein Sorcin interact and protect cells against apoptosis induced by antiblastic agents, Cancer Res 70 (2010) 6577-6586.
[31]X.D. Li, L. Sun, R.B. Seth, G. Pineda, Z.J. Chen, Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity, Proc Natl Acad Sci U S A 102 (2005) 17717-17722.
[32]K.M. Graef, F.T. Vreede, Y.F. Lau, A.W. McCall, S.M. Carr, K. Subbarao, E. Fodor, The PB2 subunit of the influenza virus RNA polymerase affects virulence by interacting with the mitochondrial antiviral signaling protein and inhibiting expression of beta interferon, J Virol 84 (2010) 8433-8445.
[33]M. Kumar, S.Y. Jung, A.J. Hodgson, C.R. Madden, J. Qin, B.L. Slagle, Hepatitis B Virus Regulatory HBx Protein Binds to Adaptor Protein IPS-1 and Inhibits the Activation of Beta Interferon, J Virol 85 (2011) 987-995.
[34]C. Wei, C. Ni, T. Song, Y. Liu, X. Yang, Z. Zheng, Y. Jia, Y. Yuan, K. Guan, Y. Xu, X. Cheng, Y. Zhang, Y. Wang, C. Wen, Q. Wu, W. Shi, H. Zhong, The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein, J Immunol 185 (2010) 1158-1168.
[35]S. Yu, J. Chen, M. Wu, H. Chen, N. Kato, Z. Yuan, Hepatitis B virus polymerase inhibits RIG-I- and Toll-like receptor 3-mediated beta interferon induction in human hepatocytes through interference with interferon regulatory factor 3 activation and dampening of the interaction between TBK1/IKKepsilon and DDX3, J Gen Virol 91 (2010) 2080-2090.
[36]S. Sharma, B.R. tenOever, N. Grandvaux, G.P. Zhou, R. Lin, J. Hiscott, Triggering the interferon antiviral response through an IKK-related pathway, Science 300 (2003) 1148-1151.
[37]Z. Lu, T. Hunter, Degradation of activated protein kinases by ubiquitination, Annu Rev Biochem 78 (2009) 435-475.
[38]N. Kishore, Q.K. Huynh, S. Mathialagan, T. Hall, S. Rouw, D. Creely, G. Lange, J. Caroll, B. Reitz, A. Donnelly, H. Boddupalli, R.G. Combs, K. Kretzmer, C.S. Tripp, IKK-i and TBK-1 are enzymatically distinct from the homologous enzyme IKK-2: comparative analysis of recombinant human IKK-i, TBK-1, and IKK-2, J Biol Chem 277 (2002) 13840-13847.
[39]J. Beck, M. Nassal, Efficient Hsp90-independent in vitro activation by Hsc70 and Hsp40 of duck hepatitis B virus reverse transcriptase, an assumed Hsp90 client protein, J Biol Chem 278 (2003) 36128-36138.
[40]K. Liu, L. Qian, J. Wang, W. Li, X. Deng, X. Chen, W. Sun, H. Wei, X. Qian, Y. Jiang, F. He, Two-dimensional blue native/SDS-PAGE analysis reveals heat shock protein chaperone machinery involved in hepatitis B virus production in HepG2.2.15 cells, Mol Cell Proteomics 8 (2009) 495-505.
[41]S.M. McWhirter, B.R. Tenoever, T. Maniatis, Connecting mitochondria and innate immunity, Cell 122 (2005) 645-647.
[42]F. Cao, J.E. Tavis, Detection and characterization of cytoplasmic hepatitis B virus reverse transcriptase, J Gen Virol 85 (2004) 3353-3360.
[43]Y. Minami, Y. Kimura, H. Kawasaki, K. Suzuki, I. Yahara, The carboxy-terminal region of mammalian HSP90 is required for its dimerization and function in vivo, Mol Cell Biol 14 (1994) 1459-1464.
[44]N. Wayne, D.N. Bolon, Dimerization of Hsp90 is required for in vivo function. Design and analysis of monomers and dimers, J Biol Chem 282 (2007) 35386-35395.
[45]F. Zoulim, New insight on hepatitis B virus persistence from the study of intrahepatic viral cccDNA, J Hepatol 42 (2005) 302-308.
[46]S. Benhenda, D. Cougot, M.A. Buendia, C. Neuveut, Hepatitis B virus X protein molecular functions and its role in virus life cycle and pathogenesis, Adv Cancer Res 103 (2009) 75-109.
[47]S.F. Wieland, F.V. Chisari, Stealth and cunning:hepatitis B and hepatitis C viruses, J Virol 79 (2005) 9369-9380.
[48]J. Wu, Z. Meng, M. Jiang, R. Pei, M. Trippler, R. Broering, A. Bucchi, J.P. Sowa, U. Dittmer, D. Yang, M. Roggendorf, G. Gerken, M. Lu, J.F. Schlaak, Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells, Hepatology 49 (2009) 1132-1140.
[49]H. Wang, W.S. Ryu, Hepatitis B virus polymerase blocks pattern recognition receptor signaling via interaction with DDX3:implications for immune evasion, PLoS Pathog 6 (2010) e1000986.
[1]S. Akira, Pathogen recognition by innate immunity and its signaling, Proc Jpn Acad Ser B Phys Biol Sci 85 (2009) 143-156.
[2]S. Akira, S. Uematsu,O. Takeuchi, Pathogen recognition and innate immunity, Cell 124 (2006) 783-801.
[3]S.M. McWhirter, B.R. Tenoever, T. Maniatis, Connecting mitochondria and innate immunity, Cell 122 (2005) 645-647.
[4]E. Dixit, S. Boulant, Y. Zhang, A.S. Lee, C. Odendall, B. Shum, N. Hacohen, Z.J. Chen, S.P. Whelan, M. Fransen, M.L. Nibert, G. Superti-Furga, J.C. Kagan, Peroxisomes are signaling platforms for antiviral innate immunity, Cell 141 (2010)668-681.
[5]T. Kawai, K. Takahashi, S. Sato, C. Coban, H. Kumar, H. Kato, K.J. Ishii, O. Takeuchi, S. Akira, IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction, Nature Immunol 6 (2005) 981-988.
[6]E. Meylan, J. Curran, K. Hofmann, D. Moradpour, M. Binder, R. Bartenschlager, J. Tschopp, Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus, Nature 437 (2005) 1167-1172.
[7]R.B. Seth, L. Sun, C.K. Ea, Z.J. Chen, Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3, Cell 122 (2005) 669-682.
[8]L.G. Xu, Y.Y. Wang, K.J. Han, L.Y. Li, Z. Zhai, H.B. Shu, VISA is an adapter protein required for virus-triggered IFN-beta signaling, Mol Cell 19 (2005) 727-740.
[9]E.D. Tang, C.Y. Wang, MAVS self-association mediates antiviral innate immune signaling, J Virol 83 (2009) 3420-3428.
[10]M. Baril, M.E. Racine, F. Penin, D. Lamarre, MAVS dimer is a crucial signaling component of innate immunity and the target of hepatitis C virus NS3/4A protease, J Virol 83 (2009) 1299-1311.
[11]C. Wei, C. Ni, T. Song, Y. Liu, X. Yang, Z. Zheng, Y. Jia, Y. Yuan, K. Guan, Y. Xu, X. Cheng, Y. Zhang, Y. Wang, C. Wen, Q. Wu, W. Shi, H. Zhong, The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein, J Immunol 185 (2010) 1158-1168.
[12]S. Paz, M. Vilasco, M. Arguello, Q. Sun, J. Lacoste, T.L. Nguyen, T. Zhao, E.A. Shestakova, S. Zaari, A. Bibeau-Poirier, M.J. Servant, R. Lin, E.F. Meurs, J. Hiscott, Ubiquitin-regulated recruitment of IkappaB kinase epsilon to the MAVS interferon signaling adapter, Mol Cell Biol 29 (2009) 3401-3412.
[13]K. Onoguchi, K. Onomoto, S. Takamatsu, M. Jogi, A. Takemura, S. Morimoto, I. Julkunen, H. Namiki, M. Yoneyama, T. Fujita, Virus-infection or 5'ppp-RNA activates antiviral signal through redistribution of IPS-1 mediated by MFN1, PLoS pathogens 6 (2010) e1001012.
[14]C. Castanier, D. Garcin, A. Vazquez, D. Arnoult, Mitochondrial dynamics regulate the RIG-I-like receptor antiviral pathway, EMBO Reports 11 (2010) 133-138.
[15]M. Schroder, Viruses and the human DEAD-box helicase DDX3:inhibition or exploitation?, Biochem Soc Trans 39 (2011) 679-683.
[16]M. Schroder, M. Baran, A.G. Bowie, Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKepsilon-mediated IRF activation, EMBO J 27 (2008) 2147-2157.
[17]D. Soulat, T. Burckstummer, S. Westermayer, A. Goncalves, A. Bauch, A. Stefanovic, O. Hantschel, K.L. Bennett, T. Decker, G. Superti-Furga, The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response, EMBO J 27 (2008) 2135-2146.
[18]H. Oshiumi, K. Sakai, M. Matsumoto, T. Seya, DEAD/H BOX 3 (DDX3) helicase binds the RIG-I adaptor IPS-1 to up-regulate IFN-beta-inducing potential, Eur J Immunol 40 (2010) 940-948.
[19]T. Song, C. Wei, Z. Zheng, Y. Xu, X. Cheng, Y. Yuan, K. Guan, Y. Zhang, Q. Ma, W. Shi, H. Zhong, c-Abl tyrosine kinase interacts with MAVS and regulates innate immune response, FEBS letters 584 (2010) 33-38.
[20]Y.Y. Wang, L.J. Liu, B. Zhong, T.T. Liu, Y. Li, Y. Yang, Y. Ran, S. Li, P. Tien, H.B. Shu, WDR5 is essential for assembly of the VISA-associated signaling complex and virus-triggered IRF3 and NF-kappaB activation, Proc Natl Acad Sci US A 107 (2010) 815-820.
[21]C.B. Moore, D.T. Bergstralh, J.A. Duncan, Y. Lei, T.E. Morrison, A.G. Zimmermann, M.A. Accavitti-Loper, V.J. Madden, L. Sun, Z. Ye, J.D. Lich, M.T. Heise, Z. Chen, J.P. Ting, NLRX1 is a regulator of mitochondrial antiviral immunity, Nature 451 (2008) 573-577.
[22]F. You, H. Sun, X. Zhou, W. Sun, S. Liang, Z. Zhai, Z. Jiang, PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4, Nature Immunol 10 (2009) 1300-1308.
[23]D. Vitour, S. Dabo, M. Ahmadi Pour, M. Vilasco, P.O. Vidalain, Y. Jacob, M. Mezel-Lemoine, S. Paz, M. Arguello, R. Lin, F. Tangy, J. Hiscott, E.F. Meurs, Polo-like kinase 1 (PLK1) regulates interferon (IFN) induction by MAVS, J Biol Chem 284 (2009) 21797-21809.
[24]K. Yasukawa, H. Oshiumi, M. Takeda, N. Ishihara, Y. Yanagi, T. Seya, S. Kawabata, T. Koshiba, Mitofusin 2 inhibits mitochondrial antiviral signaling, Science Signaling 2 (2009) ra47.
[25]X.D. Li, L. Sun, R.B. Seth, G. Pineda, Z.J. Chen, Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity, Proc Natl Acad Sci U S A 102 (2005) 17717-17722.
[26]Y. Yang, Y. Liang, L. Qu, Z. Chen, M. Yi, K. Li, S.M. Lemon, Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursor, Proc Natl Acad Sci USA104 (2007) 7253-7258.
[27]M. Rebsamen, E. Meylan, J. Curran, J. Tschopp, The antiviral adaptor proteins Cardif and Trif are processed and inactivated by caspases, Cell Death Differentiation 15 (2008) 1804-1811.
[28]I. Scott, K.L. Norris, The mitochondrial antiviral signaling protein, MAVS, is cleaved during apoptosis, Biochem Biophys Res Commun 375 (2008) 101-106.
[29]A. Iwai, T. Shiozaki, T. Kawai, S. Akira, Y. Kawaoka, A. Takada, H. Kida, T. Miyazaki, Influenza A virus polymerase inhibits type I interferon induction by binding to interferon beta promoter stimulator 1, J Biol Chem 285 (2010) 32064-32074.
[30]K.M. Graef, F.T. Vreede, Y.F. Lau, A.W. McCall, S.M. Carr, K. Subbarao, E. Fodor, The PB2 subunit of the influenza virus RNA polymerase affects virulence by interacting with the mitochondrial antiviral signaling protein and inhibiting expression of beta interferon, J Virol 84 (2010) 8433-8445.
[31]M. Kumar, S.Y. Jung, A.J. Hodgson, C.R. Madden, J. Qin, B.L. Slagle, Hepatitis B Virus Regulatory HBx Protein Binds to Adaptor Protein IPS-1 and Inhibits the Activation of Beta Interferon, J Virol 85 (2011) 987-995.