Zeng Qiongzhen, Chen Zixin, Li Shan, Huang Ziwei, Ren Zhe, Ye Cuifang, Wang Xiao, Zhou Jun, Liu Kaisheng, Zheng Kai, Wang Yifei
Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University), 518020, Shenzhen, China.
Institute of Biomedicine, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Key Laboratory of Innovative Technology Research on Natural Products and Cosmetics Raw Materials, Jinan University, 510632, Guangzhou, China.
EMBO Rep. 2025 Feb;26(3):720-747. doi: 10.1038/s44319-024-00358-5. Epub 2025 Jan 2.
Histone deacetylase HDAC6 has been implicated in regulating antiviral innate immunity. However, its precise function in response to DNA virus infection remains elusive. Herein, we find that HDAC6 deficiency promotes the activation of cGAS-STING signaling and type I interferon (IFN) production, both in vitro and in vivo, resulting in a decrease in HSV-1 infection. Mechanistically, HDAC6 deacetylates tripartite motif protein 56 (TRIM56) at K110 in mice, thereby impairing the monoubiquitination cGAS and its DNA binding ability. Overexpression of TRIM56 K110Q protects mice against HSV-1 infection. Notably, different amino acids at position 110 of TRIM56 in human and mouse cause species-specific IFN responses. Further, we show that during early stages of HSV-1 infection, the viral protein US3 phosphorylates HDAC6 to inhibit the cGAS-mediated antiviral response. Our results suggest that HDAC6 inhibits cGAS activation through TRIM56 deacetylation in a species-specific manner.
组蛋白去乙酰化酶HDAC6已被证明参与调节抗病毒天然免疫。然而，其在应对DNA病毒感染时的确切功能仍不清楚。在此，我们发现HDAC6缺陷在体外和体内均促进cGAS-STING信号通路的激活和I型干扰素（IFN）的产生，从而导致单纯疱疹病毒1型（HSV-1）感染减少。机制上，HDAC6使小鼠中的三联基序蛋白56（TRIM56）在K110位点去乙酰化，从而损害cGAS的单泛素化及其DNA结合能力。TRIM56 K110Q的过表达可保护小鼠免受HSV-1感染。值得注意的是，人和小鼠中TRIM56第110位的不同氨基酸会导致物种特异性的IFN反应。此外，我们表明在HSV-1感染的早期阶段，病毒蛋白US3使HDAC6磷酸化以抑制cGAS介导的抗病毒反应。我们的结果表明，HDAC6以物种特异性方式通过TRIM56去乙酰化抑制cGAS激活。
