The ER membrane adaptor ERAdP senses the bacterial second messenger c-di-AMP and initiates anti-bacterial immunity.
The ER membrane adaptor ERAdP senses the bacterial second messenger c-di-AMP and initiates anti-bacterial immunity.
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ER 膜适配器 ERAdP 感知细菌第二信使 c-di-AMP 并启动抗菌免疫。
DOI：
10.1038/s41590-017-0014-x
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发表时间：
2018
影响因子：
30.5
通讯作者：
Fan Zusen
中科院分区：
文献类型：
--
作者：
Xia Pengyan;Wang Shuo;Xiong Zhen;Zhu Xiaoxiao;Ye Buqing;Du Ying;Meng Shu;Qu Yuan;Liu Jing;Gao Guangxia;Tian Yong;Fan Zusen
环二腺苷酸单磷酸（c-di-AMP）是细菌分泌的第二信使。免疫细胞如何检测c-di-AMP并启动抗细菌免疫仍然未知。我们发现，内质网（ER）膜适配器ERAdP作为一个直接传感器的c-di-AMP。ERAdP缺陷小鼠对单核细胞增生李斯特菌感染高度敏感，并表现出促炎细胞因子减少。从机制上讲，c-di-AMP与ERAdP的C-末端结构域结合，进而导致ERAdP的二聚化，导致与激酶TAK 1的结合和激活。TAK 1的激活因此启动了转录因子NF-κB的激活，从而诱导先天免疫细胞中促炎细胞因子的产生。此外，ERAdP和TAK 1的双敲除导致对L的敏感性增加。单核细胞增多症因此，ERAdP介导的促炎细胞因子的产生对于控制细菌感染是至关重要的。
Cyclic diadenylate monophosphate (c-di-AMP) is secreted by bacteria as a secondary messenger. How immune cells detect c-di-AMP and initiate anti-bacterial immunity remains unknown. We found that the endoplasmic reticulum (ER) membrane adaptor ERAdP acts as a direct sensor for c-di-AMP. ERAdP-deficient mice were highly susceptible toListeria monocytogenesinfection and exhibited reduced pro-inflammatory cytokines. Mechanistically, c-di-AMP bound to the C-terminal domain of ERAdP, which in turn led to dimerization of ERAdP, resulting in association with and activation of the kinase TAK1. TAK1 activation consequently initiated activation of the transcription factor NF-κB to induce the production of pro-inflammatory cytokines in innate immune cells. Moreover, double-knockout of ERAdP and TAK1 resulted in heightened susceptibility toL. monocytogenesinfection. Thus, ERAdP-mediated production of pro-inflammatory cytokines is critical for controlling bacterial infection.