Yersinia YopJ negatively regulates IRF3-mediated antibacterial response through disruption of STING-mediated cytosolic DNA signaling

Yersinia YopJ negatively regulates IRF3-mediated antibacterial response through disruption of STING-mediated cytosolic DNA signaling

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 Delta YopJ/Yopi bacteria induced lower levels of IRF3 and IFN-beta, decreased inflammation and reduced staining of STING as compared to Delta YopJ and AYopJ/Yop.1 Cl 72A strains infection. The data herein reveal a previously unrecognized mechanism by which YopJ modulates innate immune signaling. (C) 2016 Elsevier B.V. All rights reserved.

耶尔森菌外膜蛋白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，可作为一种去泛素化酶，使多个信号通路中的若干靶点去泛素化。干扰素基因刺激因子（STING）是诱导干扰素调节因子3（IRF3）磷酸化以及随后在细胞质中对核酸作出反应产生细胞因子的关键衔接蛋白。我们的研究表明，YopJ以STING为靶标来抑制IRF3信号通路。具体而言，YopJ与STING相互作用以阻断其从内质网到高尔基体的运输，并去除其K63连接的泛素化链。去泛素化的STING扰乱了STING - TBK1复合物的形成以及IRF3的激活。YopJ的第172位半胱氨酸介导了STING去泛素化和IRF3信号抑制。因此，与ΔYopJ和AYopJ/Yop.1 Cl 72A菌株感染相比，感染野生型（WT）和ΔYopJ/Yopi细菌的小鼠诱导出较低水平的IRF3和干扰素 - β，炎症减轻且STING染色减少。本文的数据揭示了一种先前未被认识的YopJ调节先天免疫信号的机制。（C）2016爱思唯尔有限公司。保留所有权利。