RIPLET, and not TRIM25, is required for endogenous RIG-I-dependent antiviral responses
RIPLET, and not TRIM25, is required for endogenous RIG-I-dependent antiviral responses
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DOI：
10.1111/imcb.12284
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发表时间：
2019-08-19
影响因子：
4
通讯作者：
Nicholson, Sandra E.
中科院分区：
文献类型：
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作者：
Hayman, Thomas J.;Hsu, Alan C.;Nicholson, Sandra E.
先天免疫系统是我们抵御病毒病原体的第一道防线。宿主细胞模式识别受体感知病毒组件并启动免疫信号级联反应，从而产生一系列细胞因子来对抗感染。维甲酸诱导基因-I(RIG-I)是一种识别病毒RNA的模式识别受体，当被激活时，导致I型和III型干扰素(IFN)的产生和干扰素刺激基因的上调。含有25个基序的E3连接酶(TRIM25)和Riplet泛素化RIG-I被认为是RIG-I激活所必需的；然而，最近的研究质疑这两种酶对RIG-I信号转导的相对重要性。在本研究中，我们发现Trim25的缺失并不影响干扰素对甲型流感病毒(IAV)、乙型流感病毒、仙台病毒或几种RIG-I激动剂的反应。这与rig-I或Riplet的缺失形成对比，Rig-I或Riplet的缺失完全取消了rig-I依赖的干扰素反应。这在小鼠和人类细胞系中是一致的，在正常的人支气管细胞中也是如此。由于目前大多数TRIM25文献都是基于外源表达，这些发现提供了关键证据，表明Rig-I的泛素化需要Riplet，而不是TRIM25。尽管如此，失去TRIM25会导致体内对IAV感染的易感性增加，这表明它可能在宿主抗病毒防御中具有替代作用。这项研究加深了我们对RIG-I信号在病毒感染中的理解，并将为该领域的未来研究提供信息。
The innate immune system is our first line of defense against viral pathogens. Host cell pattern recognition receptors sense viral components and initiate immune signaling cascades that result in the production of an array of cytokines to combat infection. Retinoic acid-inducible gene-I (RIG-I) is a pattern recognition receptor that recognizes viral RNA and, when activated, results in the production of type I and III interferons (IFNs) and the upregulation of IFN-stimulated genes. Ubiquitination of RIG-I by the E3 ligases tripartite motif-containing 25 (TRIM25) and Riplet is thought to be requisite for RIG-I activation; however, recent studies have questioned the relative importance of these two enzymes for RIG-I signaling. In this study, we show that deletion of Trim25 does not affect the IFN response to either influenza A virus (IAV), influenza B virus, Sendai virus or several RIG-I agonists. This is in contrast to deletion of either Rig-i or Riplet, which completely abrogated RIG-I-dependent IFN responses. This was consistent in both mouse and human cell lines, as well as in normal human bronchial cells. With most of the current TRIM25 literature based on exogenous expression, these findings provide critical evidence that Riplet, and not TRIM25, is required endogenously for the ubiquitination of RIG-I. Despite this, loss of TRIM25 results in greater susceptibility to IAV infection in vivo, suggesting that it may have an alternative role in host antiviral defense. This study refines our understanding of RIG-I signaling in viral infections and will inform future studies in the field.