Human hepatitis B virus surface and e antigens inhibit major vault protein signaling in interferon induction pathways
Human hepatitis B virus surface and e antigens inhibit major vault protein signaling in interferon induction pathways
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DOI：
10.1016/j.jhep.2014.11.035
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发表时间：
2015-05-01
影响因子：
25.7
通讯作者：
Zhu, Ying
中科院分区：
文献类型：
--
作者：
Liu, Shi;Peng, Nanfang;Zhu, Ying
背景与目的：MVP是一种新的病毒诱导的宿主因子，其表达可上调I型干扰素的产生，导致细胞抗病毒反应。然而，目前尚不清楚MVP在乙肝病毒感染过程中的抗病毒功能是否受损，涉及的机制如何。因此，本研究的目的是评估在缺乏I型干扰素诱导的情况下，乙肝病毒是否能够改变MVP的表达，并阐明乙肝病毒利用其逃避宿主天然免疫反应的潜在机制。方法：通过免疫共沉淀、免疫荧光、定量RT-PCR、Western印迹和报告分析，评价乙肝表面抗原和e抗原在干扰素诱导途径中抑制MVP信号的能力。结果：在我们目前的研究中，我们发现乙肝病毒感染者的外周血单个核细胞、血清和肝组织中的MVP水平高于健康人。我们确定MVP在细胞内与MyD88结合，MyD88是一种参与病毒触发的I型干扰素诱导的接头蛋白。蛋白质截断分析表明，MVP的中间结构域(氨基酸残基310-620)是MyD88结合所必需的。相反，乙肝病毒通过抑制MVP/MyD88相互作用而抑制MVP诱导的I型干扰素的产生。结论：MVP是一种病毒诱导的蛋白，可与MyD88结合，导致I型干扰素的产生。乙肝病毒可能通过破坏这种相互作用和限制I型干扰素的抗病毒活性来逃避免疫反应。(C)2015年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background & Aims: We previously demonstrated that major vault protein (MVP) is a novel virus-induced host factor and its expression upregulates type-I interferon production, leading to cellular antiviral response. However, it remains unclear whether the antiviral function of MVP is impaired during hepatitis B virus (HBV) infection and what mechanisms are involved. Therefore, the aim of this study was to assess whether HBV can alter MVP expression despite the lack of type-I IFN induction and shed light on the underlying mechanisms HBV utilizes to evade host innate immune response.Methods: The ability of HBV surface and e antigens to inhibit MVP signaling in interferon induction pathways was evaluated by co-immunoprecipitation, immunofluorescence, quantitative RT-PCR, Western blot and reporter assays.Results: In our current study, we found high levels of MVP in peripheral blood mononuclear cells, sera, and liver tissue from HBV-infected patients relative to healthy individuals. We determined that MVP intracellularly associates with MyD88, an adapter protein involved in virus-triggered induction of type-I IFN. Protein truncation analysis revealed that the middle domain of MVP (amino acid residues 310-620) was essential for MyD88 binding. Conversely, HBV inhibited MVP-induced type-I IFN production by suppressing MVP/MyD88 interaction. HBV antigens, both HBsAg and HBeAg, suppressed this interaction by competitively binding to the essential MyD88 binding region of MVP and limiting downstream IFN signaling.Conclusions: MVP is a virus-induced protein capable of binding with MyD88 leading to type-I IFN production. HBV may evade an immune response by disrupting this interaction and limiting type-I IFN antiviral activity. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.