Viral immune modulators perturb the human molecular network by common and unique strategies
Viral immune modulators perturb the human molecular network by common and unique strategies
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DOI：
10.1038/nature11289
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发表时间：
2012-07-26
期刊：
影响因子：
64.8
通讯作者：
Superti-Furga, Giulio
中科院分区：
文献类型：
--
作者：
Pichlmair, Andreas;Kandasamy, Kumaran;Superti-Furga, Giulio
病毒必须进入宿主细胞进行复制、组装和繁殖。由于其基因组的大小有限，病毒不得不进化出利用宿主细胞过程的有效方法，以促进其自身的生命周期，并逃避宿主的免疫防御机制（1，2）。已在一系列病毒类别中发现了许多具有对病毒有效生长至关重要的免疫调节功能的病毒开放阅读框架（viORF）（3，4）。然而，还没有全面的研究来鉴定这些viORF与之相互作用的宿主因子，以用于病毒干扰策略的全局视角（5-11）。在这里，我们表明，不同的病毒扰动模式的主机分子防御网络可以推导出一个基于质谱的主机因子调查在一个确定的人类细胞系统中使用70先天免疫调节viORF从30种病毒。viORF靶向的579种宿主蛋白质映射到出乎意料的大量信号传导途径和细胞过程，表明抗病毒免疫的未知机制。我们进一步通过实验验证了靶点异质核核糖核蛋白U、磷脂酰肌醇-3-OH激酶、WNK（无赖氨酸）激酶家族和USP 19（泛素特异性肽酶19）作为宿主细胞防御系统中的脆弱节点。病毒免疫调节剂对宿主分子网络的影响的评估揭示了单个病毒和病毒类别所使用的扰动策略。我们的数据对于设计广泛和特异性的抗病毒治疗也很有价值。
Viruses must enter host cells to replicate, assemble and propagate. Because of the restricted size of their genomes, viruses have had to evolve efficient ways of exploiting host cell processes to promote their own life cycles and also to escape host immune defence mechanisms(1,2). Many viral open reading frames (viORFs) with immune-modulating functions essential for productive viral growth have been identified across a range of viral classes(3,4). However, there has been no comprehensive study to identify the host factors with which these viORFs interact for a global perspective of viral perturbation strategies(5-11). Here we show that different viral perturbation patterns of the host molecular defence network can be deduced from a mass-spectrometry-based host-factor survey in a defined human cellular system by using 70 innate immune-modulating viORFs from 30 viral species. The 579 host proteins targeted by the viORFs mapped to an unexpectedly large number of signalling pathways and cellular processes, suggesting yet unknown mechanisms of antiviral immunity. We further experimentally verified the targets heterogeneous nuclear ribonucleoprotein U, phosphatidylinositol-3-OH kinase, the WNK (with-no-lysine) kinase family and USP19 (ubiquitin-specific peptidase 19) as vulnerable nodes in the host cellular defence system. Evaluation of the impact of viral immune modulators on the host molecular network revealed perturbation strategies used by individual viruses and by viral classes. Our data are also valuable for the design of broad and specific antiviral therapies.