KAT8 selectively inhibits antiviral immunity by acetylating IRF3
KAT8 selectively inhibits antiviral immunity by acetylating IRF3
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KAT8 通过乙酰化 IRF3 选择性抑制抗病毒免疫
DOI：
10.1084/jem.20181773
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发表时间：
2019-04-01
影响因子：
15.3
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
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作者：
Huai, Wanwan;Liu, Xingguang;Cao, Xuetao
转录因子干扰素调节因子3(IRF3)在病毒感染触发的I型干扰素(IFN-I)诱导和先天性免疫反应中起着至关重要的作用。IRF3的活性受到传统的翻译后修饰(PTM)的严格调控，如磷酸化和泛素化。在这里，我们确定了IRF3的一种非传统的PTM，它直接抑制其转录活性，并减弱抗病毒免疫反应。我们进行了RNA干扰筛选，发现赖氨酸乙酰转移酶8(KAT8)在免疫细胞(特别是巨噬细胞)中普遍表达，它选择性地抑制巨噬细胞和树突状细胞中RNA和DNA病毒触发的干扰素-I的产生。KAT8缺乏通过增加干扰素-I的产生来保护小鼠免受病毒攻击。从机制上讲，KAT8直接与IRF3相互作用，并通过其myst结构域介导IRF3在赖氨酸359位的乙酰化。KAT8抑制IRF3向干扰素-I基因启动子的募集，并降低IRF3的转录活性。我们的研究揭示了KAT8和IRF3赖氨酸乙酰化在抑制抗病毒天然免疫中的关键作用。
The transcription factor interferon regulatory factor 3 (IRF3) is essential for virus infection-triggered induction of type I interferons (IFN-I) and innate immune responses. IRF3 activity is tightly regulated by conventional posttranslational modifications (PTMs) such as phosphorylation and ubiquitination. Here, we identify an unconventional PTM of IRF3 that directly inhibits its transcriptional activity and attenuates antiviral immune response. We performed an RNA interference screen and found that lysine acetyltransferase 8 (KAT8), which is ubiquitously expressed in immune cells (particularly in macrophages), selectively inhibits RNA and DNA virus-triggered IFN-I production in macrophages and dendritic cells. KAT8 deficiency protects mice from viral challenge by enhancing IFN-I production. Mechanistically, KAT8 directly interacts with IRF3 and mediates IRF3 acetylation at lysine 359 via its MYST domain. KAT8 inhibits IRF3 recruitment to IFN-I gene promoters and decreases the transcriptional activity of IRF3. Our study reveals a critical role for KAT8 and IRF3 lysine acetylation in the suppression of antiviral innate immunity.