病毒 DNA 与 NLRC3（一种抑制性核酸传感器）结合，激活 STING（一种环状二核苷酸受体），从而激活 I 型干扰素。
Viral DNA Binding to NLRC3, an Inhibitory Nucleic Acid Sensor, Unleashes STING, a Cyclic Dinucleotide Receptor that Activates Type I Interferon.
机构信息
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Oral and Craniofacial Biomedicine PhD Program, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
出版信息
Immunity. 2019 Mar 19;50(3):591-599.e6. doi: 10.1016/j.immuni.2019.02.009.
Abstract
Immune suppression is a crucial component of immunoregulation and a subgroup of nucleotide-binding domain (NBD), leucine-rich repeat (LRR)-containing proteins (NLRs) attenuate innate immunity. How this inhibitory function is controlled is unknown. A key question is whether microbial ligands can regulate this inhibition. NLRC3 is a negative regulator that attenuates type I interferon (IFN-I) response by sequestering and attenuating stimulator of interferon genes (STING) activation. Here, we report that NLRC3 binds viral DNA and other nucleic acids through its LRR domain. DNA binding to NLRC3 increases its ATPase activity, and ATP-binding by NLRC3 diminishes its interaction with STING, thus licensing an IFN-I response. This work uncovers a mechanism wherein viral nucleic acid binding releases an inhibitory innate receptor from its target.
摘要
免疫抑制是免疫调节的一个关键组成部分，核苷酸结合域（NBD）、富含亮氨酸重复序列（LRR）的蛋白质（NLRs）亚群减弱先天免疫。目前尚不清楚如何控制这种抑制功能。一个关键问题是微生物配体是否可以调节这种抑制。NLRC3 是一种负调节剂，通过隔离和减弱干扰素基因刺激物（STING）的激活来减弱 I 型干扰素（IFN-I）反应。在这里，我们报告 NLRC3 通过其 LRR 结构域与病毒 DNA 和其他核酸结合。DNA 与 NLRC3 的结合增加了其 ATP 酶活性，而 NLRC3 的 ATP 结合减少了其与 STING 的相互作用，从而许可 IFN-I 反应。这项工作揭示了一种机制，即病毒核酸结合将抑制性先天受体从其靶标中释放出来。
相似文献
1
Viral DNA Binding to NLRC3, an Inhibitory Nucleic Acid Sensor, Unleashes STING, a Cyclic Dinucleotide Receptor that Activates Type I Interferon.病毒 DNA 与 NLRC3（一种抑制性核酸传感器）结合，激活 STING（一种环状二核苷酸受体），从而激活 I 型干扰素。
Immunity. 2019 Mar 19;50(3):591-599.e6. doi: 10.1016/j.immuni.2019.02.009.
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
The Scaffolding Protein IQGAP1 Interacts with NLRC3 and Inhibits Type I IFN Production.支架蛋白IQGAP1与NLRC3相互作用并抑制I型干扰素的产生。
J Immunol. 2017 Oct 15;199(8):2896-2909. doi: 10.4049/jimmunol.1601370. Epub 2017 Sep 1.
4
Mechanisms and pathways of innate immune activation and regulation in health and cancer.健康与癌症中固有免疫激活和调节的机制与途径。
Hum Vaccin Immunother. 2014;10(11):3270-85. doi: 10.4161/21645515.2014.979640.
5
Positive feedback regulation of type I interferon by the interferon-stimulated gene STING.干扰素刺激基因STING对I型干扰素的正反馈调节
EMBO Rep. 2015 Feb;16(2):202-12. doi: 10.15252/embr.201439366. Epub 2015 Jan 8.
6
The Innate Immune Sensor NLRC3 Acts as a Rheostat that Fine-Tunes T Cell Responses in Infection and Autoimmunity.天然免疫传感器 NLRC3 作为变阻器，可精细调节感染和自身免疫中的 T 细胞反应。
Immunity. 2018 Dec 18;49(6):1049-1061.e6. doi: 10.1016/j.immuni.2018.10.008.
7
Novel chemical compound SINCRO with dual function in STING-type I interferon and tumor cell death pathways.新型化学化合物 SINCRO 在 STING 型 I 干扰素和肿瘤细胞死亡途径中具有双重功能。
Cancer Sci. 2018 Sep;109(9):2687-2696. doi: 10.1111/cas.13726. Epub 2018 Aug 1.
8
NLRC3 puts the brakes on STING.NLRC3 给 STING 踩了刹车。
Immunity. 2014 Mar 20;40(3):305-6. doi: 10.1016/j.immuni.2014.02.007.
9
The cGas-Sting Signaling Pathway Is Required for the Innate Immune Response Against Ectromelia Virus.cGas-Sting 信号通路是先天免疫反应对抗细小病毒的必需条件。
Front Immunol. 2018 Jun 14;9:1297. doi: 10.3389/fimmu.2018.01297. eCollection 2018.
10
Mitochondria in innate immune signaling.线粒体在先天免疫信号中的作用。
Transl Res. 2018 Dec;202:52-68. doi: 10.1016/j.trsl.2018.07.014. Epub 2018 Aug 7.
引用本文的文献
1
An invertebrate NLR recognizes viral nucleic acids and balances the antiviral signaling pathway through interaction with STING and Cyclophilin A.一种无脊椎动物NLR可识别病毒核酸，并通过与STING和亲环素A相互作用来平衡抗病毒信号通路。
PLoS Pathog. 2025 Aug 18;21(8):e1013433. doi: 10.1371/journal.ppat.1013433. eCollection 2025 Aug.
2
Innate immune mechanisms of infection: what we know and potential conserved mechanisms affecting sleep during infection.感染的固有免疫机制：我们所了解的以及感染期间影响睡眠的潜在保守机制。
Neurobiol Sleep Circadian Rhythms. 2025 Apr 21;18(Suppl):100121. doi: 10.1016/j.nbscr.2025.100121. eCollection 2025 May.
3
Pattern recognition receptors: function, regulation and therapeutic potential.模式识别受体：功能、调控及治疗潜力
Signal Transduct Target Ther. 2025 Jul 11;10(1):216. doi: 10.1038/s41392-025-02264-1.
4
Role of NLRC3 in modulating inflammatory responses in neonates.NLRC3在调节新生儿炎症反应中的作用。
BMC Pediatr. 2025 May 28;25(1):428. doi: 10.1186/s12887-025-05766-7.
5
Unveiling the crossroads of STING signaling pathway and metabolic reprogramming: the multifaceted role of the STING in the TME and new prospects in cancer therapies.揭示STING信号通路与代谢重编程的交叉点：STING在肿瘤微环境中的多面作用及癌症治疗新前景
Cell Commun Signal. 2025 Apr 7;23(1):171. doi: 10.1186/s12964-025-02169-0.
6
Viral protease binds to nucleosomal DNA and cleaves nuclear cGAS that attenuates type I interferon.病毒蛋白酶与核小体DNA结合并切割核内cGAS，从而减弱I型干扰素。
mBio. 2025 Apr 9;16(4):e0339524. doi: 10.1128/mbio.03395-24. Epub 2025 Feb 25.
7
Innate Immunity Never "NODs" Off: NLRs Regulate the Host Anti-Viral Immune Response.固有免疫从不“打盹”：NLRs调节宿主抗病毒免疫反应。
Immunol Rev. 2025 Mar;330(1):e13429. doi: 10.1111/imr.13429.
8
NLRC3 Attenuates Antiviral Innate Immune Response by Targeting IRF7 in Grass Carp ().NLRC3通过靶向草鱼中的IRF7减弱抗病毒天然免疫反应（）。
Int J Mol Sci. 2025 Jan 20;26(2):840. doi: 10.3390/ijms26020840.
9
Regulation of cGAS-STING signalling and its diversity of cellular outcomes.cGAS-STING信号通路的调控及其细胞结果的多样性。
Nat Rev Immunol. 2025 Jan 7. doi: 10.1038/s41577-024-01112-7.
10
Viral sepsis: diagnosis, clinical features, pathogenesis, and clinical considerations.病毒性脓毒症：诊断、临床特征、发病机制及临床考量
Mil Med Res. 2024 Dec 16;11(1):78. doi: 10.1186/s40779-024-00581-0.
本文引用的文献
1
The Innate Immune Sensor NLRC3 Acts as a Rheostat that Fine-Tunes T Cell Responses in Infection and Autoimmunity.天然免疫传感器 NLRC3 作为变阻器，可精细调节感染和自身免疫中的 T 细胞反应。
Immunity. 2018 Dec 18;49(6):1049-1061.e6. doi: 10.1016/j.immuni.2018.10.008.
2
The NLRP6 Inflammasome Recognizes Lipoteichoic Acid and Regulates Gram-Positive Pathogen Infection.NLRP6 炎性体识别脂磷壁酸并调节革兰阳性菌感染。
Cell. 2018 Nov 29;175(6):1651-1664.e14. doi: 10.1016/j.cell.2018.09.047. Epub 2018 Nov 1.
3
NLRC3 negatively regulates CD4+ T cells and impacts protective immunity during Mycobacterium tuberculosis infection.NLRC3 负向调节 CD4+T 细胞，并影响结核分枝杆菌感染期间的保护性免疫。
PLoS Pathog. 2018 Aug 22;14(8):e1007266. doi: 10.1371/journal.ppat.1007266. eCollection 2018 Aug.
4
New mitochondrial DNA synthesis enables NLRP3 inflammasome activation.新的线粒体 DNA 合成使 NLRP3 炎症小体激活。
Nature. 2018 Aug;560(7717):198-203. doi: 10.1038/s41586-018-0372-z. Epub 2018 Jul 25.
5
The Scaffolding Protein IQGAP1 Interacts with NLRC3 and Inhibits Type I IFN Production.支架蛋白IQGAP1与NLRC3相互作用并抑制I型干扰素的产生。
J Immunol. 2017 Oct 15;199(8):2896-2909. doi: 10.4049/jimmunol.1601370. Epub 2017 Sep 1.
6
NLRC3 protein inhibits inflammation by disrupting NALP3 inflammasome assembly via competition with the adaptor protein ASC for pro-caspase-1 binding.NLRC3蛋白通过与衔接蛋白ASC竞争结合前半胱天冬酶-1，破坏NALP3炎性小体组装，从而抑制炎症。
J Biol Chem. 2017 Jul 28;292(30):12691-12701. doi: 10.1074/jbc.M116.769695. Epub 2017 Jun 5.
7
NLRC3 is an inhibitory sensor of PI3K-mTOR pathways in cancer.NLRC3是癌症中PI3K-mTOR信号通路的一种抑制性感受器。
Nature. 2016 Dec 22;540(7634):583-587. doi: 10.1038/nature20597. Epub 2016 Dec 12.
8
Crystal structure of NOD2 and its implications in human disease.NOD2 结构及其与人类疾病的关系
Nat Commun. 2016 Jun 10;7:11813. doi: 10.1038/ncomms11813.
9
Modeling-Enabled Characterization of Novel NLRX1 Ligands.基于建模的新型NLRX1配体的表征
PLoS One. 2015 Dec 29;10(12):e0145420. doi: 10.1371/journal.pone.0145420. eCollection 2015.
10
GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation.GROMACS 4：高效、负载均衡和可扩展的分子模拟算法。
J Chem Theory Comput. 2008 Mar;4(3):435-47. doi: 10.1021/ct700301q.
Zotero 插件