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标题: 邓红雨课题组发现丙型肝炎病毒逃逸免疫反应的新机制 [打印本页]

作者: rentianyixu    时间: 2015-11-30 21:49
标题: 邓红雨课题组发现丙型肝炎病毒逃逸免疫反应的新机制
 丙型肝炎病毒(hepatitis C virus, HCV)是引起丙型肝炎传染性疾病的病原体,严重危害人类健康。天然免疫反应是机体抵抗病毒感染的第一道防线。HCV感染宿主细胞后,可被天然免疫系统识别,激活干扰素信号通路,进一步诱导下游一系列干扰素刺激基因的表达而发挥直接抗病毒功能。但同时HCV又可通过多种策略抑制和逃避宿主的抗病毒活性,保持其在靶细胞中的复制,造成宿主的持续性感染。目前全球约1.3-1.7亿人携带HCV,说明这种病毒已建立有效机制来逃避和抵抗宿主的免疫反应,但是其中的许多分子机制尚不清楚。因此,深入探讨病毒与宿主天然免疫系统之间的相互作用,将有助于深入理解HCV逃避免疫反应并实现持续性感染的分子机制,对设计和开发药物具有重要的指导意义。
  2015年11月17日,Science Signaling 期刊在线发表了中国科学院生物物理研究所邓红雨课题组题为“The hepatitis C virus protein NS3 suppresses TNF-α–stimulated activation of NF-κB by targeting LUBAC”的研究成果,揭示了HCV通过抑制TNF-α诱导的NF-κB激活而实现免疫逃逸的一种新机制。
  邓红雨课题组的主要研究方向为致瘤病毒与宿主的相互作用。临床数据表明,丙肝病毒感染者的血液中会有较高浓度的肿瘤坏死因子TNF-α,这是由巨噬细胞、单核细胞等活化产生的一种细胞因子,通常情况下会激活在天然免疫反应中起重要作用的NF-κB信号,从而帮助机体抵抗病毒感染,但丙肝病毒感染者体内的NF-κB信号却处于受抑制的状态。邓红雨课题组的研究显示,这一令人费解的临床现象与一种叫NS3的HCV非结构蛋白有关。LUBAC(linear ubiquitin chain assembly complex)为NF-κB信号通路上的一个关键调控蛋白复合物,通过与IKK复合物中的NEMO结合并使NEMO线性泛素化,进而激活下游的NF-κB信号。HCV的NS3蛋白通过与LUBAC相互作用,竞争性地阻碍了LUBAC与NEMO的结合,使NEMO不能线性泛素化,最终导致NF-κB的激活受到抑制,从而帮助HCV完成免疫逃逸。在此前的研究中,课题组还鉴定了胆固醇25羟化酶(CH25H,一种干扰素诱导基因产物)的抗HCV功能,并阐明了其作用机制(Chen et al., Scientific Reports 2014)。这些工作揭示了病毒与宿主天然免疫系统之间的精彩博弈。
  该论文第一作者为已毕业博士生陈勇志,在读博士生贺亮和彭亚男等参与了部分研究工作,邓红雨研究员和海外团队程根宏教授为该论文的共同通讯作者。武汉病毒研究所陈新文研究员和上海巴斯德研究所钟劲研究员为该工作提供了重要试剂。该研究得到了科技部973项目和国家自然科学基金委杰出青年基金项目的资助。   
  
  图:丙型肝炎病毒与宿主天然免疫系统之间的精彩博弈(Chen et al., Science Signaling 2015; Chen et al., Scientific Reports 2014)。
  文章链接:
  http://stke.sciencemag.org/content/8/403/ra118.long
  http://www.ibp.cas.cn/denghylab/denghylabkycg/201407/W020151119383889282859.pdf

  供稿:邓红雨课题组


作者: rentianyixu    时间: 2015-11-30 21:50
Sci Signal. 2015 Nov 17;8(403):ra118. doi: 10.1126/scisignal.aab2159.

The hepatitis C virus protein NS3 suppresses TNF-α-stimulated activation of NF-κB by targeting LUBAC.
Chen Y1, He L1, Peng Y1, Shi X2, Chen J3, Zhong J4, Chen X3, Cheng G5, Deng H6.
Author information
1CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China. University of Chinese Academy of Sciences, Beijing 100049, China.
2CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China.
3State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
4Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200025, China.
5CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China. Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. hydeng@moon.ibp.ac.cn gcheng@mednet.ucla.edu.
6CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China. hydeng@moon.ibp.ac.cn gcheng@mednet.ucla.edu.

Abstract
The transcription factor nuclear factor κB (NF-κB) is crucial for innate immune defense against viral infections, and its activation requires the ubiquitylation of upstream proteins, including the adaptor protein NEMO (NF-κB essential modulator). Many infectious pathogens, including hepatitis C virus (HCV), inhibit NF-κB signaling in host cells, which promotes pathogen survival. Frequently, HCV-infected individuals develop a chronic infection, which suggests that HCV can subvert host antiviral responses. We found that HCV infection and replication inhibited the activation of NF-κB by the inflammatory cytokine tumor necrosis factor-α (TNF-α), which was mediated by the viral protein NS3 and, to a lesser extent, NS5B. NS3 directly interacted with linear ubiquitin chain assembly complex (LUBAC), competed with NEMO for binding to LUBAC, and inhibited the LUBAC-mediated linear ubiquitylation of NEMO and the subsequent activation of NF-κB. Together, our results highlight an immune evasion strategy adopted by HCV to modulate host antiviral responses and enhance virus survival and persistence.
作者: dalc999    时间: 2015-12-1 00:13
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