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The ER membrane adaptor ERAdP senses the bacterial second messenger c-di-AMP and initiates anti-bacterial immunity.
Nature Immunology ( IF 27.7 ) Pub Date : 2018-Feb-01 , DOI: 10.1038/s41590-017-0014-x
Pengyan Xia , Shuo Wang , Zhen Xiong , Xiaoxiao Zhu , Buqing Ye , Ying Du , Shu Meng , Yuan Qu , Jing Liu , Guangxia Gao , Yong Tian , Zusen Fan

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 to Listeria monocytogenes infection 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 to L. monocytogenes infection. Thus, ERAdP-mediated production of pro-inflammatory cytokines is critical for controlling bacterial infection.

中文翻译:

ER膜适配器ERAdP感应细菌第二信使c-di-AMP并启动抗菌免疫力。

细菌分泌环二腺苷酸单磷酸酯(c-di-AMP)作为次级信使。免疫细胞如何检测c-di-AMP并启动抗菌免疫仍是未知的。我们发现内质网(ER)膜适配器ERAdP充当c-di-AMP的直接传感器。ERAdP缺陷的小鼠高度易受李斯特菌感染,并表现出降低的促炎细胞因子。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,从而导致TAK1激酶与之结合并活化。因此,TAK1激活启动了转录因子NF-κB的激活,以诱导先天免疫细胞中促炎性细胞因子的产生。此外,ERAdP和TAK1的双重敲除导致对L的敏感性增加。单核细胞增生病感染。因此,ERAdP介导的促炎性细胞因子的产生对于控制细菌感染至关重要。
更新日期:2018-01-01
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