Cao Ye, Guan Kai, He Xiang, Wei Congwen, Zheng Zirui, Zhang Yanhong, Ma Shengli, Zhong Hui, Shi Wei
Key Laboratory for Molecular Enzymology & Engineering, the Ministry of Education, Jilin University, Changchun 130012, China; College of Life Science, Jilin University, Changchun 130012, China; State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, China.
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, China.
Biochim Biophys Acta. 2016 Dec;1863(12):3148-3159. doi: 10.1016/j.bbamcr.2016.10.004. Epub 2016 Oct 11.
The Yersinia outer protein J (YopJ) plays a pivotal role in evading the host immune response and establishes a persistent infection in host cells after bacterial infection. YopJ is a cysteine protease and can act as a deubiquitinating enzyme that deubiquitinates several targets in multiple signaling pathways. Stimulator of interferon genes (STING) is a critical adapter for the induction of interferon regulatory factor 3 (IRF3) phosphorylation and subsequent production of the cytokines in response to nucleic acids in the cytoplasm. Our studies demonstrate that YopJ targets STING to inhibit IRF3 signaling. Specially, YopJ interacts with STING to block its ER-to-Golgi traffic and remove its K63-linked ubiquitination chains. Deubiquited STING perturbs the formation of STING-TBK1 complex and the activation of IRF3. The 172th cysteine of YopJ mediated STING deubiquitination and IRF3 signaling inhibition. Consequently, mice infected with WT and ΔYopJ/YopJ bacteria induced lower levels of IRF3 and IFN-β, decreased inflammation and reduced staining of STING as compared to ΔYopJ and ΔYopJ/YopJ C172A strains infection. The data herein reveal a previously unrecognized mechanism by which YopJ modulates innate immune signaling.
耶尔森氏菌外蛋白J（YopJ）在逃避宿主免疫反应中起关键作用，并在细菌感染后在宿主细胞中建立持续感染。YopJ是一种半胱氨酸蛋白酶，可作为去泛素化酶，使多个信号通路中的多个靶标去泛素化。干扰素基因刺激因子（STING）是诱导干扰素调节因子3（IRF3）磷酸化以及随后响应细胞质中的核酸产生细胞因子的关键衔接蛋白。我们的研究表明，YopJ靶向STING以抑制IRF3信号传导。具体而言，YopJ与STING相互作用，阻断其从内质网到高尔基体的转运，并去除其K63连接的泛素化链。去泛素化的STING扰乱了STING-TBK1复合物的形成和IRF3的激活。YopJ的第172位半胱氨酸介导了STING的去泛素化和IRF3信号传导的抑制。因此，与感染ΔYopJ和ΔYopJ/YopJ C172A菌株相比，感染野生型和ΔYopJ/YopJ细菌的小鼠诱导的IRF3和IFN-β水平较低，炎症减轻，STING染色减少。本文的数据揭示了一种以前未被认识的YopJ调节先天免疫信号传导的机制。
