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, encoding 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 GMP-AMP synthase (cGAS), and enhanced interferon signaling mediated by the cGAS-stimulator of interferon genes (STING) pathway in patient fibroblasts. Finally, we established that chromatin without linker histone more efficiently stimulates cGAS production in vitro. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA.
In mammals, the three classical ras genes encode four highly homologous proteins, N-Ras, H-Ras, and the isoforms K-Ras 4A and 4B. Previous studies have shown that K-ras is essential for mouse development and that while K-ras 4A and 4B are expressed during development, K-ras 4A expression is regulated temporally and spatially and occurs in adult kidney, intestine, stomach, and liver. In the present study, the pattern of K-ras 4A expression was examined in a wide range of wild-type adult mouse tissues, and gene targeting was used to generate K-ras 4A-deficient mice to examine its role in development. It was found that K-ras 4A is also expressed in uterus, lung, pancreas, salivary glands, seminal vesicles, bone marrow cells, and cecum, where it was the major K-Ras isoform expressed. Mating between K-ras tm⌬4A/؉ mice produced viable K-ras tm⌬4A/tm⌬4A offspring with the expected Mendelian ratios of inheritance, and these mice expressed the K-ras 4B splice variant only. K-ras tm⌬4A/tm⌬4A mice were fertile and showed no histopathological abnormalities on inbred (129/Ola) or crossbred (129/Ola ؋ C57BL/6) genetic backgrounds. The results demonstrate that K-Ras 4A, like H-and N-Ras, is dispensable for normal mouse development, at least in the presence of functional K-Ras 4B.
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