Wang Chunmei, Wang Qinlan, Xu Xiaoqing, Xie Bin, Zhao Yong, Li Nan, Cao Xuetao
Department of Immunology and Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China.
J Exp Med. 2017 Dec 4;214(12):3597-3610. doi: 10.1084/jem.20170856. Epub 2017 Nov 3.
Lysine methylation is an important posttranslational modification, implicated in various biological pathological conditions. The transcription factor interferon regulatory factor 3 (IRF3) is essential for antiviral innate immunity, yet the mechanism for methylation control of IRF3 activation remains unclear. In this paper, we discovered monomethylation of IRF3 at K366 is critical for IRF3 transcription activity in antiviral innate immunity. By mass spectrometry analysis of IRF3-associated proteins, we identified nuclear receptor-binding SET domain 3 (NSD3) as the lysine methyltransferase that directly binds to the IRF3 C-terminal region through its PWWP1 domain and methylates IRF3 at K366 via its SET domain. Deficiency of NSD3 impairs the antiviral innate immune response in vivo Mechanistically, NSD3 enhances the transcription activity of IRF3 dependent on K366 monomethylation, which maintains IRF3 phosphorylation by promoting IRF3 dissociation of protein phosphatase PP1cc and consequently promotes type I interferon production. Our study reveals a critical role of NSD3-mediated IRF3 methylation in enhancing antiviral innate immunity.
赖氨酸甲基化是一种重要的翻译后修饰，与多种生物病理状况有关。转录因子干扰素调节因子3（IRF3）对抗病毒天然免疫至关重要，然而IRF3激活的甲基化控制机制仍不清楚。在本文中，我们发现IRF3第366位赖氨酸的单甲基化对抗病毒天然免疫中IRF3的转录活性至关重要。通过对与IRF3相关蛋白的质谱分析，我们鉴定出核受体结合SET结构域3（NSD3）为赖氨酸甲基转移酶，其通过PWWP1结构域直接与IRF3的C末端区域结合，并通过SET结构域使IRF3第366位赖氨酸发生甲基化。NSD3的缺失会损害体内抗病毒天然免疫反应。从机制上讲，NSD3通过依赖于K366单甲基化增强IRF3的转录活性，通过促进IRF3与蛋白磷酸酶PP1cc解离来维持IRF3的磷酸化，从而促进I型干扰素的产生。我们的研究揭示了NSD3介导的IRF3甲基化在增强抗病毒天然免疫中的关键作用。
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