A diverse range of gene products are effectors of the type I interferon antiviral response.
A diverse range of gene products are effectors of the type I interferon antiviral response.
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DOI：
10.1038/nature09907
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发表时间：
2011-04-28
期刊：
影响因子：
64.8
通讯作者：
Rice, Charles M.
中科院分区：
文献类型：
--
作者：
Schoggins, John W.;Wilson, Sam J.;Panis, Maryline;Murphy, Mary Y.;Jones, Christopher T.;Bieniasz, Paul;Rice, Charles M.
I 型干扰素 (IFN) 反应可保护细胞免受病毒病原体的入侵。介导这种防御的细胞因子是干扰素刺激基因（ISG）的产物。尽管自 25 年前发现以来，已鉴定出数百种 ISG，但只有少数 ISG 具有抗病毒活性。对于大多数人来说，对其抗病毒潜力、靶标特异性及其作用机制知之甚少。使用过表达筛选方法，我们发现不同的病毒被独特的 ISG 组所针对，每种病毒物种都容易受到具有一系列抑制活性的多种抗病毒基因的影响。为了进行筛选，测试了超过 380 种 ISG 抑制多种重要病毒复制的能力，包括丙型肝炎病毒 (HCV)、黄热病病毒 (YFV)、西尼罗河病毒 (WNV)、基孔肯雅病毒 (CHIKV)、委内瑞拉马脑炎病毒 (VEEV) 和人类免疫缺陷病毒 (HIV-1)。广泛作用的效应器包括 IRF1、C6orf150、HPSE、RIG-I、MDA5 和 IFITM3，而 DDX60、IFI44L、IFI6、IFITM2、MAP3K14、MOV10、NAMPT、OASL、RTP4、TREX1 和 UNC84B 则观察到更有针对性的抗病毒特异性。两个 ISG 对的联合表达显示出与中等剂量 IFN 相似的附加抗病毒作用。机制研究揭示了许多效应子的翻译抑制的共同主题。 ADAR、FAM46C、LY6E 和 MCOLN2 等多种 ISG 增强了某些病毒的复制，凸显了高度多效性 IFN 系统的另一层复杂性。
The type I interferon (IFN) response protects cells from invading viral pathogens. The cellular factors that mediate this defense are the products of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified since their discovery over 25 years ago, only few have been characterized with respect to antiviral activity. For most, little is known about their antiviral potential, their target specificity, and their mechanisms of action. Using an overexpression screening approach, we show that different viruses are targeted by unique sets of ISGs, with each viral species susceptible to multiple antiviral genes with a range of inhibitory activities. To conduct the screen, over 380 ISGs were tested for their ability to inhibit the replication of several important viruses including hepatitis C virus (HCV), yellow fever virus (YFV), West Nile virus (WNV), chikungunya virus (CHIKV), Venezuelan equine encephalitis virus (VEEV), and human immunodeficiency virus (HIV-1). Broadly acting effectors included IRF1, C6orf150, HPSE, RIG-I, MDA5, and IFITM3, while more targeted antiviral specificity was observed with DDX60, IFI44L, IFI6, IFITM2, MAP3K14, MOV10, NAMPT, OASL, RTP4, TREX1, and UNC84B. Combined expression of two-ISG pairs showed additive antiviral effects similar to moderate IFN doses. Mechanistic studies revealed a common theme of translational inhibition for numerous effectors. Several ISGs, including ADAR, FAM46C, LY6E, and MCOLN2, enhanced replication of certain viruses, highlighting another layer of complexity in the highly pleiotropic IFN system.
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