通过cGAS-STING途径进行双链DNA感知的机制。
The mechanism of double-stranded DNA sensing through the cGAS-STING pathway.
作者信息
Shu Chang, Li Xin, Li Pingwei
机构信息
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843-2128, USA.
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843-2128, USA.
出版信息
Cytokine Growth Factor Rev. 2014 Dec;25(6):641-8. doi: 10.1016/j.cytogfr.2014.06.006. Epub 2014 Jun 22.
Abstract
Microbial nucleic acids induce potent innate immune responses by stimulating the expression of type I interferons. Cyclic GMP-AMP synthase (cGAS) is a cytosolic dsDNA sensor mediating the innate immunity to microbial DNA. cGAS is activated by dsDNA and catalyze the synthesis of a cyclic dinucleotide cGAMP with 2',5' and 3',5'phosphodiester linkages. cGAMP binds to the adaptor STING located on the endoplasmic reticulum membrane and mediates the recruitment and activation of the protein kinase TBK1 and transcription factor IRF3. Phosphorylated IRF3 translocates to the nucleus and initiates the transcription of the IFN-β gene. The crystal structures of cGAS and its complex with dsDNA, STING and its complex with various cyclic dinucleotides have been determined recently. Here we summarize the results from these structural studies and provide an overview about the mechanism of cGAS activation by dsDNA, the catalytic mechanism of cGAS, and the structural basis of STING activation by cGAMP.
摘要
微生物核酸通过刺激I型干扰素的表达诱导强烈的先天免疫反应。环磷酸鸟苷-腺苷合成酶（cGAS）是一种胞质双链DNA传感器，介导对微生物DNA的先天免疫。cGAS被双链DNA激活，并催化合成具有2',5'和3',5'磷酸二酯键的环二核苷酸cGAMP。cGAMP与位于内质网膜上的衔接蛋白STING结合，并介导蛋白激酶TBK1和转录因子IRF3的募集和激活。磷酸化的IRF3易位至细胞核并启动IFN-β基因的转录。最近已经确定了cGAS及其与双链DNA的复合物、STING及其与各种环二核苷酸的复合物的晶体结构。在这里，我们总结了这些结构研究的结果，并概述了双链DNA激活cGAS的机制、cGAS的催化机制以及cGAMP激活STING的结构基础。
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本文引用的文献
1
Innate immune sensing and signaling of cytosolic nucleic acids.细胞质核酸的先天免疫感应和信号转导。
Annu Rev Immunol. 2014;32:461-88. doi: 10.1146/annurev-immunol-032713-120156.
2
NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING.NLRC3，NLR 蛋白家族的一员，是 DNA 传感器 STING 诱导的固有免疫信号的负调节剂。
Immunity. 2014 Mar 20;40(3):329-41. doi: 10.1016/j.immuni.2014.01.010. Epub 2014 Feb 20.
3
Crosstalk between the cGAS DNA sensor and Beclin-1 autophagy protein shapes innate antimicrobial immune responses.cGAS DNA 传感器与 Beclin-1 自噬蛋白之间的串扰塑造了先天抗微生物免疫反应。
Cell Host Microbe. 2014 Feb 12;15(2):228-38. doi: 10.1016/j.chom.2014.01.009.
4
The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop.细胞质 DNA 传感器 cGAS 与 DNA 形成寡聚复合物，并在激活环中发生类似开关的构象变化。
Cell Rep. 2014 Feb 13;6(3):421-30. doi: 10.1016/j.celrep.2014.01.003. Epub 2014 Jan 23.
5
Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced oligomerization.环鸟苷酸-腺苷酸合酶可被双链 DNA 诱导的寡聚化激活。
Immunity. 2013 Dec 12;39(6):1019-31. doi: 10.1016/j.immuni.2013.10.019.
6
cGAS dimerization entangles DNA recognition.cGAS 二聚化使 DNA 识别纠缠。
Immunity. 2013 Dec 12;39(6):992-4. doi: 10.1016/j.immuni.2013.11.012.
7
STING-dependent cytosolic DNA sensing pathways.STING 依赖性胞质 DNA 感应途径。
Trends Immunol. 2014 Feb;35(2):88-93. doi: 10.1016/j.it.2013.10.010. Epub 2013 Dec 2.
8
Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity.IFN 诱导基因的泛病毒特异性揭示 cGAS 在先天免疫中的新作用。
Nature. 2014 Jan 30;505(7485):691-5. doi: 10.1038/nature12862. Epub 2013 Nov 27.
9
Single nucleotide polymorphisms of human STING can affect innate immune response to cyclic dinucleotides.人类 STING 的单核苷酸多态性可以影响对环状二核苷酸的先天免疫反应。
PLoS One. 2013 Oct 21;8(10):e77846. doi: 10.1371/journal.pone.0077846. eCollection 2013.
10
Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling.环状二核苷酸触发 ULK1（ATG1）对 STING 的磷酸化，以防止持续的先天免疫信号转导。
Cell. 2013 Oct 24;155(3):688-98. doi: 10.1016/j.cell.2013.09.049. Epub 2013 Oct 10.
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