The N-Ethyl-N-Nitrosourea-Induced Goldenticket Mouse Mutant Reveals an Essential Function of Sting in the In Vivo Interferon Response to Listeria monocytogenes and Cyclic Dinucleotides
The N-Ethyl-N-Nitrosourea-Induced Goldenticket Mouse Mutant Reveals an Essential Function of Sting in the In Vivo Interferon Response to Listeria monocytogenes and Cyclic Dinucleotides
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DOI：
10.1128/iai.00999-10
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发表时间：
2011-02-01
影响因子：
3.1
通讯作者：
Vance, Russell E.
中科院分区：
文献类型：
--
作者：
Sauer, John-Demian;Sotelo-Troha, Katia;Vance, Russell E.
I型干扰素（ifn）是对病毒和细菌感染的先天和适应性免疫反应的中枢调节因子。I型ifn是通过细胞质检测微生物核酸（包括DNA、RNA和细菌第二信使环二gmp (c-di-GMP)）诱导产生的。此外，最近的一项研究表明，由于胞质检测到细菌分泌的c-di-AMP，细胞内细菌病原体单核增生李斯特菌刺激I型IFN反应。跨膜信号接头Sting （Tmem173, Mita, Mpys, Eris）最近被认为与I型ifn的诱导有关，以响应胞质DNA和/或RNA。然而，Sting在对纯化的环二核苷酸或体内单核细胞增生乳杆菌感染的反应中所起的作用尚未得到解决。为了确定在先天免疫应答中重要的基因，我们使用诱变剂n -乙基-n -亚硝基脲（ENU）对C57BL/6小鼠进行了正向基因诱变筛选。在这里，我们描述了一种新的突变小鼠菌株，Goldenticket (Gt)，在单核细胞增生乳杆菌感染后不能产生I型ifn。通过遗传定位和互补实验，我们发现Gt小鼠携带Sting的单核苷酸变异（T596A），该变异作为一个空等位基因，不能产生可检测的蛋白质。从Gt小鼠分离的巨噬细胞分析显示，对于I型干扰素对c-di-GMP和c-di-AMP的应答，Sting是绝对必需的。此外，在体内对c-di-GMP和L.单核细胞增生的反应需要Sting。我们的研究结果为Sting在先天干扰素对病原体的反应中提供了新的功能。
Type I interferons (IFNs) are central regulators of the innate and adaptive immune responses to viral and bacterial infections. Type I IFNs are induced upon cytosolic detection of microbial nucleic acids, including DNA, RNA, and the bacterial second messenger cyclic-di-GMP (c-di-GMP). In addition, a recent study demonstrated that the intracellular bacterial pathogen Listeria monocytogenes stimulates a type I IFN response due to cytosolic detection of bacterially secreted c-di-AMP. The transmembrane signaling adaptor Sting (Tmem173, Mita, Mpys, Eris) has recently been implicated in the induction of type I IFNs in response to cytosolic DNA and/or RNA. However, the role of Sting in response to purified cyclic dinucleotides or during in vivo L. monocytogenes infection has not been addressed. In order to identify genes important in the innate immune response, we have been conducting a forward genetic mutagenesis screen in C57BL/6 mice using the mutagen N-ethyl-N-nitrosourea (ENU). Here we describe a novel mutant mouse strain, Goldenticket (Gt), that fails to produce type I IFNs upon L. monocytogenes infection. By genetic mapping and complementation experiments, we found that Gt mice harbor a single nucleotide variant (T596A) of Sting that functions as a null allele and fails to produce detectable protein. Analysis of macrophages isolated from Gt mice revealed that Sting is absolutely required for the type I interferon response to both c-di-GMP and c-di-AMP. Additionally, Sting is required for the response to c-di-GMP and L. monocytogenes in vivo. Our results provide new functions for Sting in the innate interferon response to pathogens.