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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.

Original publication

DOI

10.1038/s41588-020-00737-3

Type

Journal article

Journal

Nat Genet

Publication Date

12/2020

Volume

52

Pages

1364 - 1372

Keywords

Autoimmune Diseases of the Nervous System, Cell Line, Chromatin, DNA, Gene Expression Regulation, HCT116 Cells, HEK293 Cells, Hereditary Autoinflammatory Diseases, Histones, Humans, Interferon Type I, Membrane Proteins, Nervous System Malformations, Nucleotides, Cyclic, Nucleotidyltransferases, RNA Precursors, RNA-Binding Proteins, Ribonucleoprotein, U7 Small Nuclear