Alternative splicing of hepatitis B virus: A novel virus/host interaction altering liver immunity.
Alternative splicing of hepatitis B virus: A novel virus/host interaction altering liver immunity.
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DOI：
10.1016/j.jhep.2017.05.025
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发表时间：
2017-10
影响因子：
25.7
通讯作者：
Soussan P
中科院分区：
文献类型：
--
作者：
Duriez M;Mandouri Y;Lekbaby B;Wang H;Schnuriger A;Redelsperger F;Guerrera CI;Lefevre M;Fauveau V;Ahodantin J;Quetier I;Chhuon C;Gourari S;Boissonnas A;Gill U;Kennedy P;Debzi N;Sitterlin D;Maini MK;Kremsdorf D;Soussan P
B型肝炎病毒（HBV）RNA可以进行选择性剪接，但这种转录后调控的相关性仍然难以捉摸。本文就HBV选择性剪接调控机制及其对肝脏发病机制的影响进行了研究。通过RNA下拉结合质谱分析鉴定HBV RNA相互作用蛋白。在化学和手术诱导的HBV全基因组转基因小鼠和肝癌细胞中研究HBV剪接调节。通过RT-qPCR、蛋白质印迹和ELISA定量病毒和内源基因表达。通过FACS研究驻留的肝免疫细胞。HBV前基因组RNA相互作用蛋白被鉴定，15%与剪接机制直接相关。这些剪接因子的表达在肝损伤的HBV转基因小鼠中受到调节，并导致编码HBV剪接产生蛋白（HBSP）的HBV剪接RNA的增加。HBSP转基因小鼠在化学诱导的肝纤维化下表现出减轻的肝损伤。HBSP的保护作用是通过下调肝细胞产生的CCL 2表达减少炎性单核细胞/巨噬细胞的募集。在人肝癌细胞中，HBSP控制CCL 2表达的能力得到证实，并在整个HBV背景下得以维持。最后，与慢性HBV携带者肝脏中CCL 2表达减少相关的病毒剪接RNA检测强调了这一机制。肝损伤改变的微环境通过剪接因子的调节增加HBSP RNA的表达，进而控制肝细胞趋化因子的合成。这种反馈机制提示了HBV感染期间肝脏免疫发病机制的新见解。B型肝炎病毒在慢性感染患者的肝脏中持续存在数十年。这种病毒持续存在的主要机制之一是逃避免疫反应。我们的研究强调了病毒和肝脏感染细胞之间的相互作用可能有助于这种免疫逃逸。
Hepatitis B virus (HBV) RNA can undergo alternative splicing but the relevance of this post-transcriptional regulation remains elusive. Here, the mechanism of HBV alternative splicing regulation and its impact on liver pathogenesis were investigated. HBV RNA-interacting proteins were identified by RNA pull-down combined to mass spectrometry analysis. HBV splicing regulation was investigated in chemically and surgically induced liver damage in whole HBV genome transgenic mice and in hepatoma cells. Viral and endogenous gene expression were quantified by RT-qPCR, western blot and ELISA. Resident liver immune cells were studied by FACS. HBV pregenomic RNA-interacting proteins were identified and 15% were directly related to the splicing machinery. Expression of these splicing factors was modulated in HBV transgenic mice under liver injuries and contributed to an increase of the HBV spliced RNA encoding for HBV splicing-generated protein (HBSP). HBSP transgenic mice exhibited an attenuated hepatic damage under chemically induced liver fibrosis. The protective effect of HBSP resulted from a decrease of inflammatory monocyte/macrophage recruitment through a downregulation of CCL2 expression produced by hepatocytes. In human hepatoma cells, ability of HBSP to control CCL2 expression was confirmed and maintained in a whole HBV context. Finally, viral spliced RNA detection related to a decrease of CCL2 expression in liver of HBV chronic carriers underscored this mechanism. Microenvironment modified by liver injury increased HBSP RNA expression through splicing factors regulation, which in turns controlled hepatocyte chemokine synthesis. This feedback mechanism suggests a novel insight in liver immunopathogenesis during HBV infection. Hepatitis B virus persists during decades in liver of chronic infected patients. One of the main mechanisms developed by this virus to persist is to escape immune response. Our study highlights how the crosstalk between virus and liver infected cells may contribute to this immune escape.
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影响因子：
5.4
作者：
GUIDOTTI, LG;MATZKE, B;CHISARI, FV
通讯作者：
CHISARI, FV
影响因子：
30.5
作者：
Huang, Li-Rung;Wohlleber, Dirk;Knolle, Percy A.
通讯作者：
Knolle, Percy A.
DOI：
10.1016/j.bbagrm.2010.01.011
发表时间：
2010-05
影响因子：
4.7
作者：
Bayfield, Mark A.;Yang, Ruiqing;Maraia, Richard J.
通讯作者：
Maraia, Richard J.
DOI：
10.3390/v2071394
发表时间：
2010-07
期刊：
Viruses
影响因子：
--
作者：
Ait-Goughoulte M;Lucifora J;Zoulim F;Durantel D
通讯作者：
Durantel D
影响因子：
13.5
作者：
Heymann, Felix;Peusquens, Julia;Tacke, Frank
通讯作者：
Tacke, Frank