Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, New York 10065, USA.
Nature. 2011 Apr 28;472(7344):481-5. doi: 10.1038/nature09907. Epub 2011 Apr 10.
The type I interferon response protects cells against invading viral pathogens. The cellular factors that mediate this defence are the products of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified since their discovery more than 25 years ago, only a few have been characterized with respect to antiviral activity. For most ISG products, little is known about their antiviral potential, their target specificity and their mechanisms of action. Using an overexpression screening approach, here we show that different viruses are targeted by unique sets of ISGs. We find that each viral species is susceptible to multiple antiviral genes, which together encompass a range of inhibitory activities. To conduct the screen, more than 380 human ISGs were tested for their ability to inhibit the replication of several important human and animal viruses, including hepatitis C virus, yellow fever virus, West Nile virus, chikungunya virus, Venezuelan equine encephalitis virus and human immunodeficiency virus type-1. Broadly acting effectors included IRF1, C6orf150 (also known as MB21D1), HPSE, RIG-I (also known as DDX58), MDA5 (also known as IFIH1) and IFITM3, whereas more targeted antiviral specificity was observed with DDX60, IFI44L, IFI6, IFITM2, MAP3K14, MOV10, NAMPT (also known as PBEF1), OASL, RTP4, TREX1 and UNC84B (also known as SUN2). Combined expression of pairs of ISGs showed additive antiviral effects similar to those of moderate type I interferon doses. Mechanistic studies uncovered a common theme of translational inhibition for numerous effectors. Several ISGs, including ADAR, FAM46C, LY6E and MCOLN2, enhanced the replication of certain viruses, highlighting another layer of complexity in the highly pleiotropic type I interferon system.
I 型干扰素反应可保护细胞免受入侵的病毒病原体的侵害。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 年前发现以来已经鉴定了数百种 ISG，但只有少数几种在抗病毒活性方面得到了表征。对于大多数 ISG 产物，其抗病毒潜力、靶标特异性和作用机制知之甚少。在这里，我们使用过表达筛选方法表明，不同的病毒被独特的一组 ISG 靶向。我们发现每种病毒都易受多种抗病毒基因的影响，这些基因共同包含一系列抑制活性。为了进行筛选，我们测试了超过 380 个人类 ISG，以确定它们抑制几种重要的人类和动物病毒（包括丙型肝炎病毒、黄热病病毒、西尼罗河病毒、基孔肯雅病毒、委内瑞拉马脑炎病毒和人类免疫缺陷病毒-1）复制的能力。广谱作用因子包括 IRF1、C6orf150（也称为 MB21D1）、HPSE、RIG-I（也称为 DDX58）、MDA5（也称为 IFIH1）和 IFITM3，而 DDX60、IFI44L、IFI6、IFITM2、MAP3K14、MOV10、NAMPT（也称为 PBEF1）、OASL、RTP4、TREX1 和 UNC84B（也称为 SUN2）则表现出更具针对性的抗病毒特异性。ISG 的组合表达表现出与中等剂量 I 型干扰素相似的相加抗病毒作用。机制研究揭示了许多效应物的翻译抑制的共同主题。几种 ISG，包括 ADAR、FAM46C、LY6E 和 MCOLN2，增强了某些病毒的复制，突出了高度多效的 I 型干扰素系统的另一层复杂性。
