State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Protein Cell. 2021 Apr;12(4):261-278. doi: 10.1007/s13238-020-00751-5. Epub 2020 Aug 9.
TANK-binding kinase 1 (TBK1), a core kinase of antiviral pathways, activates the production of interferons (IFNs). It has been reported that deacetylation activates TBK1; however, the precise mechanism still remains to be uncovered. We show here that during the early stage of viral infection, the acetylation of TBK1 was increased, and the acetylation of TBK1 at Lys241 enhanced the recruitment of IRF3 to TBK1. HDAC3 directly deacetylated TBK1 at Lys241 and Lys692, which resulted in the activation of TBK1. Deacetylation at Lys241 and Lys692 was critical for the kinase activity and dimerization of TBK1 respectively. Using knockout cell lines and transgenic mice, we confirmed that a HDAC3 null mutant exhibited enhanced susceptibility to viral challenge via impaired production of type I IFNs. Furthermore, activated TBK1 phosphorylated HDAC3, which promoted the deacetylation activity of HDAC3 and formed a feedback loop. In this study, we illustrated the roles the acetylated and deacetylated forms of TBK1 play in antiviral innate responses and clarified the post-translational modulations involved in the interaction between TBK1 and HDAC3.
TANK 结合激酶 1（TBK1）是抗病毒途径的核心激酶，可激活干扰素（IFNs）的产生。据报道，去乙酰化可激活 TBK1；然而，确切的机制仍有待揭示。我们在这里表明，在病毒感染的早期阶段，TBK1 的乙酰化增加，并且 TBK1 赖氨酸 241 的乙酰化增强了 IRF3 向 TBK1 的募集。HDAC3 可直接在 TBK1 的赖氨酸 241 和赖氨酸 692 处进行去乙酰化，从而导致 TBK1 的激活。赖氨酸 241 和赖氨酸 692 的去乙酰化分别对 TBK1 的激酶活性和二聚化至关重要。通过使用敲除细胞系和转基因小鼠，我们证实了 HDAC3 缺失突变体通过减少 I 型 IFNs 的产生而表现出对病毒攻击的易感性增强。此外，激活的 TBK1 磷酸化了 HDAC3，促进了 HDAC3 的去乙酰化活性，并形成了一个反馈环。在这项研究中，我们说明了乙酰化和去乙酰化形式的 TBK1 在抗病毒先天免疫反应中的作用，并阐明了 TBK1 和 HDAC3 之间相互作用涉及的翻译后修饰。
