Functional dissection of an innate immune response by a genome-wide RNAi screen.
Functional dissection of an innate immune response by a genome-wide RNAi screen.
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DOI：
10.1371/journal.pbio.0020203
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发表时间：
2004-08
期刊：
影响因子：
9.8
通讯作者：
O'Farrell PH
中科院分区：
文献类型：
--
作者：
Foley E;O'Farrell PH
先天免疫系统古老且高度保守。它是绝大多数后生动物的第一道防线和唯一可识别的免疫系统。将病原体检测转化为防御反应的信号事件是先天免疫的核心。果蝇已成为研究这种调节的宝贵模型生物。 caspase-8 同源物 Dredd 激活 NF-κB 家族成员 Relish 是对革兰氏阴性菌反应中的一个核心信号模块，但人们对此仍知之甚少。为了确定有助于这种调节的基因，我们产生了与果蝇基因组中保守基因相对应的双链RNA，并将该资源用于全基因组RNA干扰筛选。我们在细胞培养模型中发现了许多免疫报告基因的抑制剂和激活剂。上位相互作用和表型定义了基因作用的层次结构，并证明保守的基因病是激活 Relish 所必需的。我们还表明，第二个基因，防御阻遏蛋白 1，编码具有凋亡蛋白抑制剂特征的产物，该蛋白抑制 Dredd caspase 以维持信号通路的静止。分子分析表明，Dredd 在反馈环路中上调防御阻遏蛋白 1。我们认为，该反馈环路的中断有助于信号转导。通过沉默果蝇中的所有保守基因，Foley 和 O'Farrell 发现了许多针对革兰氏阴性细菌先天信号反应的新调节因子
The innate immune system is ancient and highly conserved. It is the first line of defense and the only recognizable immune system in the vast majority of metazoans. Signaling events that convert pathogen detection into a defense response are central to innate immunity. Drosophila has emerged as an invaluable model organism for studying this regulation. Activation of the NF-κB family member Relish by the caspase-8 homolog Dredd is a central, but still poorly understood, signaling module in the response to gram-negative bacteria. To identify the genes contributing to this regulation, we produced double-stranded RNAs corresponding to the conserved genes in the Drosophila genome and used this resource in genome-wide RNA interference screens. We identified numerous inhibitors and activators of immune reporters in a cell culture model. Epistatic interactions and phenotypes defined a hierarchy of gene action and demonstrated that the conserved gene sickie is required for activation of Relish. We also showed that a second gene, defense repressor 1, encodes a product with characteristics of an inhibitor of apoptosis protein that inhibits the Dredd caspase to maintain quiescence of the signaling pathway. Molecular analysis revealed that Defense repressor 1 is upregulated by Dredd in a feedback loop. We propose that interruption of this feedback loop contributes to signal transduction. By silencing all conserved genes in Drosphila, Foley and O'Farrell have identified numerous new regulators of the innate signaling response to gram-negative bacteria
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影响因子：
11.8
作者：
Boutros, M;Agaisse, H;Perrimon, N
通讯作者：
Perrimon, N
影响因子：
10.5
作者：
Drier, EA;Huang, LH;Steward, R
通讯作者：
Steward, R
DOI：
10.1073/pnas.110149597
发表时间：
2000-06-06
影响因子：
11.1
作者：
Clemens, JC;Worby, CA;Dixon, JE
通讯作者：
Dixon, JE
影响因子：
16
作者：
Hedengren, M;Åsling, B;Hultmark, D
通讯作者：
Hultmark, D
影响因子：
64.5
作者：
IP, YT;REACH, M;LEVINE, M
通讯作者：
LEVINE, M