State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Jiangning District, Nanjing, China.
PLoS Pathog. 2018 Nov 2;14(11):e1007435. doi: 10.1371/journal.ppat.1007435. eCollection 2018 Nov.
Stimulator of interferon genes (STING) is critical for cytosolic DNA-triggered innate immunity. STING is modified by several types of polyubiquitin chains. Here, we report that the deubiquitinase CYLD sustains STING signaling by stabilizing the STING protein. CYLD deficiency promoted the K48-linked polyubiquitination and degradation of STING, attenuating the induction of IRF3-responsive genes after HSV-1 infection or the transfection of DNA ligands. Additionally, CYLD knockout mice were more susceptible to HSV-1 infection than their wild-type (WT) littermates. Mechanistically, STING translocated from the ER to the Golgi upon HSV-1 stimulation; CYLD partially accumulated with STING and interacted selectively with K48-linked polyubiquitin chains on STING, specifically removing the K48-linked polyubiquitin chains from STING and ultimately boosting the innate antiviral response. Our study reveals that CYLD is a novel checkpoint in the cGAS-STING signaling pathway and sheds new light on the dynamic regulation of STING activity by ubiquitination.
干扰素基因刺激物（STING）对于细胞质 DNA 触发的先天免疫至关重要。STING 被几种类型的多泛素链修饰。在这里，我们报告去泛素化酶 CYLD 通过稳定 STING 蛋白来维持 STING 信号。CYLD 缺乏促进了 STING 的 K48 连接多泛素化和降解，减弱了 HSV-1 感染或 DNA 配体转染后 IRF3 反应基因的诱导。此外，CYLD 敲除小鼠比其野生型（WT）同窝仔对 HSV-1 感染更敏感。在机制上，HSV-1 刺激后 STING 从 ER 易位到高尔基体；CYLD 部分与 STING 累积，并选择性地与 STING 上的 K48 连接多泛素链相互作用，特异性地从 STING 上去除 K48 连接多泛素链，最终增强先天抗病毒反应。我们的研究揭示了 CYLD 是 cGAS-STING 信号通路中的一个新的检查点，并为泛素化对 STING 活性的动态调节提供了新的见解。
