Shigella IpaH0722 E3 ubiquitin ligase effector targets TRAF2 to inhibit PKC-NF-κB activity in invaded epithelial cells.
Shigella IpaH0722 E3 ubiquitin ligase effector targets TRAF2 to inhibit PKC-NF-κB activity in invaded epithelial cells.
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DOI：
10.1371/journal.ppat.1003409
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Sasakawa C
中科院分区：
文献类型：
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作者：
Ashida H;Nakano H;Sasakawa C
NF-κB在调节针对细菌感染的先天性免疫应答中起核心作用。因此，许多细菌病原体部署多种机制来抵消NF-κB活化。志贺氏菌在上皮细胞内的入侵和随后的复制被各种病原体识别受体识别为病原体相关的分子模式。这些受体通过激活NF-κB信号通路触发先天防御机制。在这里，我们显示了通过使用志贺氏菌III型分泌系统递送IpaH E3泛素连接酶家族成员IpaH 0722对NF-κB活化的抑制。IpaH 0722通过泛素化TRAF 2（PKC下游分子）和促进其蛋白酶体依赖性降解，优先抑制PKC介导的NF-κB活化，从而抑制急性炎症反应。在对细菌感染的应答中，宿主细胞诱导过多的先天免疫应答以对抗感染。然而，许多细菌病原体已经发展出复杂的机制来逃避宿主的免疫系统。由于NF-κB对于针对细菌感染的先天免疫应答至关重要，细菌病原体部署多种对策来抑制NF-κB活化。志贺氏菌在宿主细胞内的侵入和复制导致细胞损伤和触发NF-κB活化的细菌组分的产生。在这里，我们表明志贺氏菌III型分泌系统（T3 SS）效应IpaH 0722，IpaH E3泛素连接酶家族的成员，抑制NF-κB活化在志贺氏菌感染。IpaH 0722优先靶向PKC-NF-κB通路，该通路在志贺氏菌传播到细胞质期间响应于由吞噬体膜破坏引起的危险信号而被激活。IpaH 0722通过靶向位于PKC下游的TRAF 2进行泛素化和蛋白酶体依赖性降解来抑制NF-κB活化。
NF-κB plays a central role in modulating innate immune responses to bacterial infections. Therefore, many bacterial pathogens deploy multiple mechanisms to counteract NF-κB activation. The invasion of and subsequent replication of Shigella within epithelial cells is recognized by various pathogen recognition receptors as pathogen-associated molecular patterns. These receptors trigger innate defense mechanisms via the activation of the NF-κB signaling pathway. Here, we show the inhibition of the NF-κB activation by the delivery of the IpaH E3 ubiquitin ligase family member IpaH0722 using Shigella's type III secretion system. IpaH0722 dampens the acute inflammatory response by preferentially inhibiting the PKC-mediated activation of NF-κB by ubiquitinating TRAF2, a molecule downstream of PKC, and by promoting its proteasome-dependent degradation. In response to bacterial infection, host cells induce a plethora of innate immune responses to combat the infection. However, many bacterial pathogens have developed sophisticated mechanisms to evade the host's immune system. Because NF-κB is crucial for innate immune responses against bacterial infection, bacterial pathogens deploy multiple countermeasures to inhibit NF-κB activation. The invasion and replication of Shigella within host cells results in cellular damage and the production of bacterial components that trigger NF-κB activation. Here, we show that the Shigella type III secretion system (T3SS) effector IpaH0722, a member of the IpaH E3 ubiquitin ligase family, inhibits NF-κB activation during Shigella infection. IpaH0722 preferentially targets the PKC–NF-κB pathway, which is activated in response to danger signals caused by disruption of the phagosomal membrane during the dissemination of Shigella into the cytoplasm. IpaH0722 inhibits NF-κB activation by targeting TRAF2, which lies downstream of PKC, for ubiquitination and proteasome-dependent degradation.
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影响因子：
29.7
作者：
Davis BK;Wen H;Ting JP
通讯作者：
Ting JP
影响因子：
3.6
作者：
Ashida, Hiroshi;Toyotome, Takahito;Sasakawa, Chihiro
通讯作者：
Sasakawa, Chihiro
细菌效应器设计和功能的常见主题。
影响因子：
30.3
作者：
Galan, Jorge E.
通讯作者：
Galan, Jorge E.
影响因子：
30.3
作者：
Hicks SW;Charron G;Hang HC;Galán JE
通讯作者：
Galán JE
DOI：
10.1038/nri2873
发表时间：
2010-12
期刊：
Nature reviews. Immunology
影响因子：
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作者：
通讯作者：
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