PNAS：陈志坚课题组发表cGAMP在自体免疫中的作用机制
PNAS：陈志坚课题组发表cGAMP在自体免疫中的作用机制来源：生物谷 2015-10-27 10:05http://cache1.bioon.com/fckup/2015/10/pharmon201510231520406135.png2015年10月27日 讯 /生物谷BIOON/ --天然免疫的识别机制一直是免疫学领域的研究热点。最近，以陈志坚教授为代表的课题组发表了可以识别胞浆中DNA的感受元件-Cyclic-GAMP synthase，该酶能够与胞内的双链DNA特异性结合，进而以ATP与GTP为底物，催化Cyclic GAMP的合成。新生成的cGAMP能够与内质网蛋白STING结合激活IKK与TBK，最终引发I型干扰素的释放。该机制成功解释了在DNA病毒感染过程中宿主对病毒核酸是如何进行识别的，但如果不加以严格控制，Cyclic-GAMP synthase会识别自身的双链DNA从而引发自体免疫反应。TREX1是一类I型核酸外切酶，临床研究发现：该编码该酶的基因的突变能够导致患者出现严重的自身免疫反应（例如系统性红斑狼疮等）。这些自身免疫疾病都有一个相似性：即患者体内出现严重的ISG（即干扰素相关基因）的表达。同样，TREX缺失突变的小鼠也出现了相似的表型。因此，研究者们猜想可能TREX1的缺失突变会激活I型干扰素的信号。对此，陈志坚研究组研究了该缺失突变引发的自体免疫疾病与cGAMP信号通路之间的关系，研究结果发表在最近一期的《PNAS》杂志上。首先，作者对TREX-/-小鼠体内的cGAS进行了再次敲除。检测结果显示：cGAS的缺失能够完全恢复TREX-/-小鼠的自体免疫致死表型。而且体内的cGAMP与ISG的表达水平也明显下降。进一步，作者比较了双突变小鼠与TERX-/-小鼠的炎症反应特征。H&E染色结果显示，cGAS的缺失能够大幅减少淋巴细胞向骨骼肌以及心脏浸润的趋势。该结果表明cGAS介导了TREX-/-小鼠多器官炎症反应。后续的生理指标检测结果显示：cGAS的缺失大幅降低了小鼠体内针对自身DNA的抗体的滴度以及效应T细胞的数量。之后，作者利用另外一个自身免疫的小鼠模型DnaseI-/-小鼠进行同样的研究，结果显示cGAS同样介导了Dnase-/-小鼠自体免疫的发生，包括cGAMP的产生以及ISG的表达。综上，作者利用一系列生理检测手段证明了cGAS不仅是针对外源感染的识别元件，同样也是引发自体免疫疾病的关键分子。这为将来设计特异性的药物靶点提供了依据。（生物谷Bioon.com）本文系生物谷原创编译整理。欢迎转载！转载请注明来源并附原文链接。更多资讯请下载生物谷资讯APP。http://cache1.bioon.com/fckup/2015/10/pharmon201510231520538062.pngdoi: 10.1073/pnas.1516465112PMC:PMID：Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseasesDaxing Gaoa, Tuo Lia, Xiao-Dong Lia, Xiang Chen, Quan-Zhen Li, Mary Wight-Carter, and Zhijian J. ChenTREX1 is an exonuclease that digests DNA in the cytoplasm. Loss-of-function mutations of TREX1 are linked to Aicardi-Goutieres Syndrome (AGS) and systemic lupus erythematosus (SLE) in humans. Trex1?/? mice exhibit autoimmune and inflammatory phenotypes that are associated with elevated expression of interferon (IFN)-induced genes (ISGs). Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that activates the IFN pathway. Upon binding to DNA, cGAS is activated to catalyze the synthesis of cGAMP, which functions as a second messenger that binds and activates the adaptor protein STING to induce IFNs and other cytokines. Here we show that genetic ablation of cGas in Trex1?/? mice eliminated all detectable pathological and molecular phenotypes, including ISG induction, autoantibody production, aberrant T-cell activation, and lethality. Even deletion of just one allele of cGas largely rescued the phenotypes of Trex1?/? mice. Similarly, deletion of cGas in mice lacking DNaseII, a lysosomal enzyme that digests DNA, rescued the lethal autoimmune phenotypes of the DNaseII?/? mice. Through quantitative mass spectrometry, we found that cGAMP accumulated in mouse tissues deficient in Trex1 or DNaseII and that this accumulation was dependent on cGAS. These results demonstrate that cGAS activation causes the autoimmune diseases in Trex1?/? and DNaseII?/? mice and suggest that inhibition of cGAS may lead to prevention and treatment of some human autoimmune diseases caused by self-DNA.
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