LINE1 contributes to autoimmunity through both RIG-I- and MDA5-mediated RNA sensing pathways
LINE1 contributes to autoimmunity through both RIG-I- and MDA5-mediated RNA sensing pathways
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LINE1 通过 RIG-I 和 MDA5 介导的 RNA 传感途径促进自身免疫
DOI：
10.1016/j.jaut.2018.02.007
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发表时间：
2018-06-01
影响因子：
12.8
通讯作者：
Yu, Xiao-Fang
中科院分区：
文献类型：
--
作者：
Zhao, Ke;Du, Juan;Yu, Xiao-Fang
不当宿主免疫激活导致自身免疫性疾病AICARDI-GOTIERES综合征（AGS）的发展，这归因于TREX1和ADAR1等蛋白质中定义的遗传突变。迄今为止，AGS患者免疫激活的机制尚未彻底阐明。在这项研究中，我们报告说，内源性LINE1成分触发多种人类细胞类型的IFNIβ产生，包括那些CGA/STING介导的DNA感应的缺陷。在这些细胞中，线1触发的免疫激活并不需要Line1 DNA合成和逆转录置，但是RNA感应途径是必不可少的。线条触发的免疫激活可以被不同的line1抑制剂抑制，包括与AGS相关的蛋白靶向线1 RNA或蛋白质。然而，与AGS相关的ADAR1或TREX1突变体在抑制Line1逆转录位置或线1触发的免疫激活方面存在缺陷。因此，我们已经揭示了Line1作为先天免疫激活的内源性触发的新功能，这对于理解基于IFN的自身免疫性疾病的分子基础很重要，并可能提供新的干预策略。 （c）2018 Elsevier Ltd.保留所有权利。
Improper host immune activation leads to the development of the autoimmune disease Aicardi-Goutieres syndrome (AGS), which is attributed to defined genetic mutations in such proteins as TREX1 and ADAR1. The mechanism of immune activation in AGS patients has not been thoroughly elucidated to date. In this study, we report that endogenous LINE1 components trigger IFNI beta production in multiple human cell types, including those defective for cGAS/STING-mediated DNA sensing. In these cells, LINE1 DNA synthesis and retrotransposition were not required for LINE1-triggered immune activation, but RNA sensing pathways were essential. LINEI-triggered immune activation could be suppressed by diverse LINE1 inhibitors, including AGS-associated proteins targeting LINE1 RNA or proteins. However, AGS-associated ADAR1 or TREX1 mutants were defective in suppressing LINE1 retrotransposition or LINE1-triggered immune activation. Therefore, we have revealed a new function for LINE1 as an endogenous trigger of innate immune activation, which is important for understanding the molecular basis of IFN-based autoimmune diseases and may offer new intervention strategies. (C) 2018 Elsevier Ltd. All rights reserved.