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–Goutières 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.

I型干扰素反应的不适当刺激或有缺陷的负调节可导致自身炎症。在 I 型干扰素病 Aicardi-Goutières 综合征的遗传无特征病例中，我们发现了LSM11和RNU7-1中的双等位基因突变，它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本的错误处理和接头组蛋白化学计量的紊乱有关。此外，我们观察到核环磷酸鸟苷-磷酸腺苷合酶 (cGAS) 分布的改变和由 cGAS-干扰素基因刺激物 (STING) 通路介导的增强的干扰素信号传导在患者来源的成纤维细胞中。最后，我们确定没有接头组蛋白的染色质在体外更有效地刺激环磷酸鸟苷 - 磷酸腺苷 (cGAMP) 的产生。我们得出结论，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。