cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing
cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing
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DOI：
10.1038/s41588-020-00737-3
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发表时间：
2020-11-23
期刊：
影响因子：
30.8
通讯作者：
Crow, Yanick J.
中科院分区：
文献类型：
--
作者：
Uggenti, Carolina;Lepelley, Alice;Crow, Yanick J.
I 型干扰素反应的不适当刺激或负调节缺陷可导致自身炎症。在遗传上未表征的 I 型干扰素病 Aicardi-Goutieres 综合征病例中，我们发现了 LSM11 和 RNU7-1 的双等位基因突变，它们编码复制依赖性组蛋白前 mRNA 加工复合物的成分。突变与典型组蛋白转录物的错误处理和连接组蛋白化学计量的紊乱有关。此外，我们在患者来源的成纤维细胞中观察到核环单磷酸鸟苷-单磷酸腺苷合酶（cGAS）分布的改变以及由cGAS干扰素基因刺激剂（STING）通路介导的干扰素信号传导增强。最后，我们确定没有连接组蛋白的染色质在体外更有效地刺激环单磷酸鸟苷-单磷酸腺苷（cGAMP）的产生。我们得出的结论是，核组蛋白作为染色质的关键成分，对于抑制自身 DNA 的免疫原性至关重要。LSM11 和 RNU7-1（编码复制依赖性组蛋白前 mRNA 加工复合物的成分）的突变，由于 cGAS-STING 通路介导的干扰素信号增强而导致自身炎症综合征，这表明核组蛋白在抑制自身 DNA 的免疫原性中发挥着重要作用。
Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutieres syndrome, we identified biallelic mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA-processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and enhanced interferon signaling mediated by the cGAS-stimulator of interferon genes (STING) pathway in patient-derived fibroblasts. Finally, we established that chromatin without linker histone stimulates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) production in vitro more efficiently. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA.Mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA-processing complex, cause an autoinflammatory syndrome due to enhanced interferon signaling mediated by the cGAS-STING pathway, showing an essential role for nuclear histones in suppressing the immunogenicity of self-DNA.