RNase H2 catalytic core Aicardi-Goutières syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice.
RNase H2 catalytic core Aicardi-Goutières syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice.
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DOI：
10.1084/jem.20151464
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发表时间：
2016-03-07
期刊：
影响因子：
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通讯作者：
Crouch RJ
中科院分区：
文献类型：
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作者：
Pokatayev V;Hasin N;Chon H;Cerritelli SM;Sakhuja K;Ward JM;Morris HD;Yan N;Crouch RJ
在神经炎性aicardii - gouti<e:1>综合征患者中发现RNase H2突变形式的小鼠会发展成一种致命的cgas - sting依赖性疾病。神经炎症性自身免疫性疾病aicardii - gouti<e:1>综合征（AGS）是由编码几种核苷酸加工蛋白（包括RNase H2）的基因突变引起的。RNase H2缺陷可诱导自身核酸物质积累，引发慢性I型干扰素和炎症反应，导致AGS病理。我们创建了一个敲入小鼠模型，在催化亚基Rnaseh2aG37S/G37S （G37S）的高度保守残基中存在RNase H2 AGS突变，以了解疾病病理。与先前报道的Rnaseh2b-或rnaseh2c -缺失小鼠的早期胚胎死亡率相反，G37S纯合子是围产期致死的。重要的是，我们发现G37S突变导致依赖于cGAS-STING信号通路的干扰素刺激基因的表达增加。G37S小鼠的STING消融可部分恢复围产期死亡率，存活小鼠腹部表面出现白色斑点。我们相信G37S敲入小鼠为研究rnaseh2相关自身免疫性疾病提供了一个很好的动物模型。
Mice with a mutated form of RNase H2 found in patients with the neuroinflammatory Aicardi-Goutières Syndrome develop a lethal, cGAS–STING–dependent disease. The neuroinflammatory autoimmune disease Aicardi-Goutières syndrome (AGS) develops from mutations in genes encoding several nucleotide-processing proteins, including RNase H2. Defective RNase H2 may induce accumulation of self-nucleic acid species that trigger chronic type I interferon and inflammatory responses, leading to AGS pathology. We created a knock-in mouse model with an RNase H2 AGS mutation in a highly conserved residue of the catalytic subunit, Rnaseh2aG37S/G37S (G37S), to understand disease pathology. G37S homozygotes are perinatal lethal, in contrast to the early embryonic lethality previously reported for Rnaseh2b- or Rnaseh2c-null mice. Importantly, we found that the G37S mutation led to increased expression of interferon-stimulated genes dependent on the cGAS–STING signaling pathway. Ablation of STING in the G37S mice results in partial rescue of the perinatal lethality, with viable mice exhibiting white spotting on their ventral surface. We believe that the G37S knock-in mouse provides an excellent animal model for studying RNASEH2-associated autoimmune diseases.