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核糖核酸酶H2突变可诱导cGAS/STING依赖性先天免疫反应。

Ribonuclease H2 mutations induce a cGAS/STING-dependent innate immune response.

作者信息

Mackenzie Karen J, Carroll Paula, Lettice Laura, Tarnauskaitė Žygimantė, Reddy Kaalak, Dix Flora, Revuelta Ailsa, Abbondati Erika, Rigby Rachel E, Rabe Björn, Kilanowski Fiona, Grimes Graeme, Fluteau Adeline, Devenney Paul S, Hill Robert E, Reijns Martin Am, Jackson Andrew P

机构信息

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.

Roslin Institute, The University of Edinburgh, Edinburgh, UK.

出版信息

EMBO J. 2016 Apr 15;35(8):831-44. doi: 10.15252/embj.201593339. Epub 2016 Feb 22.

DOI:10.15252/embj.201593339
PMID:26903602
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4855687/
Abstract

Aicardi-Goutières syndrome (AGS) provides a monogenic model of nucleic acid-mediated inflammation relevant to the pathogenesis of systemic autoimmunity. Mutations that impair ribonuclease (RNase) H2 enzyme function are the most frequent cause of this autoinflammatory disorder of childhood and are also associated with systemic lupus erythematosus. Reduced processing of eitherRNA:DNAhybrid or genome-embedded ribonucleotide substrates is thought to lead to activation of a yet undefined nucleic acid-sensing pathway. Here, we establishRnaseh2b(A174T/A174T)knock-in mice as a subclinical model of disease, identifying significant interferon-stimulated gene (ISG) transcript upregulation that recapitulates theISGsignature seen inAGSpatients. The inflammatory response is dependent on the nucleic acid sensor cyclicGMP-AMPsynthase (cGAS) and its adaptorSTINGand is associated with reduced cellular ribonucleotide excision repair activity and increasedDNAdamage. This suggests thatcGAS/STINGis a key nucleic acid-sensing pathway relevant toAGS, providing additional insight into disease pathogenesis relevant to the development of therapeutics for this childhood-onset interferonopathy and adult systemic autoimmune disorders.

摘要

艾卡迪 - 古铁雷斯综合征（AGS）提供了一种与系统性自身免疫发病机制相关的核酸介导炎症的单基因模型。损害核糖核酸酶（RNase）H2酶功能的突变是这种儿童自身炎症性疾病最常见的病因，并且还与系统性红斑狼疮相关。RNA:DNA杂交体或基因组嵌入的核糖核苷酸底物的加工减少被认为会导致尚未明确的核酸感应途径的激活。在此，我们建立了Rnaseh2b（A174T/A174T）基因敲入小鼠作为疾病的亚临床模型，发现显著的干扰素刺激基因（ISG）转录上调，重现了在AGS患者中看到的ISG特征。炎症反应依赖于核酸传感器环磷酸鸟苷 - 腺苷合酶（cGAS）及其接头蛋白STING，并且与细胞核糖核苷酸切除修复活性降低和DNA损伤增加相关。这表明cGAS/STING是与AGS相关的关键核酸感应途径，为与这种儿童期发病的干扰素病和成人系统性自身免疫性疾病治疗开发相关的疾病发病机制提供了更多见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/531b/4972136/7802c290e9fc/EMBJ-35-831-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/531b/4972136/72eb69955521/EMBJ-35-831-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/531b/4972136/45c094eca4c9/EMBJ-35-831-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/531b/4972136/75b1fcabc61e/EMBJ-35-831-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/531b/4972136/6ea03693c700/EMBJ-35-831-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/531b/4972136/7802c290e9fc/EMBJ-35-831-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/531b/4972136/72eb69955521/EMBJ-35-831-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/531b/4972136/45c094eca4c9/EMBJ-35-831-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/531b/4972136/75b1fcabc61e/EMBJ-35-831-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/531b/4972136/6ea03693c700/EMBJ-35-831-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/531b/4972136/7802c290e9fc/EMBJ-35-831-g006.jpg

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