Bacterial E3 Ubiquitin Ligase IpaH4.5 of Shigella flexneri Targets TBK1 To Dampen the Host Antibacterial Response
Bacterial E3 Ubiquitin Ligase IpaH4.5 of Shigella flexneri Targets TBK1 To Dampen the Host Antibacterial Response
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福氏志贺氏菌的细菌 E3 泛素连接酶 IpaH4.5 靶向 TBK1 抑制宿主抗菌反应
DOI：
10.4049/jimmunol.1501045
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
He Xiang
中科院分区：
文献类型：
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作者：
Zheng Zirui;Wei Congwen;Guan Kai;Yuan Yuan;Zhang Yanhong;Ma Shengli;Cao Ye;Wang Fang;Zhong Hui;He Xiang
干扰素调节因子在许多细胞过程中发挥关键作用，包括炎症和免疫反应。它们的激活受坦克结合蛋白1(TBK1)的严格调控。作为对微生物成分的响应，TBK1激活了干扰素调节因子3(IRF3)和细胞因子的表达。在这篇文章中，我们证明了TBK1是IpaH4.5蛋白的一个新靶点，IpaH4.5蛋白是一种具有E3泛素连接酶活性的III型志贺氏菌效应器。值得注意的是，IpaH4.5与TBK1相互作用，并促进其K48连接的多泛素化。因此，多泛素化的TBK1经历了依赖于蛋白酶体的降解，这扰乱了IRF3的磷酸化、核转位和激活。由于IRF3和TBK1是限制志贺氏菌生长所必需的，我们认为在志贺氏菌感染过程中TBK1的多泛素化和降解是调节宿主抗菌反应的新的细菌策略。
IFN regulatory factors play a pivotal role in many cellular processes, including inflammatory and immune responses. Their activation is tightly regulated by TANK-binding kinase 1 (TBK1). In response to microbial components, TBK1 activates IFN regulatory factor 3 (IRF3) and cytokine expression. In this article, we show that TBK1 is a novel target of the IpaH4.5 protein, a Shigella type III effector possessing E3 ubiquitin ligase activity. Remarkably, IpaH4.5 interacts with TBK1 and promotes its K48-linked polyubiquitylation. Consequently, polyubiquitylated TBK1 undergoes proteasome-dependent degradation, which perturbs the phosphorylation, nuclear translocation, and activation of IRF3. Because IRF3 and TBK1 are required for restricting Shigella growth, we propose that the polyubiquitylation and degradation of TBK1 during Shigella infection are new bacterial strategies to modulate the host antibacterial responses.