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Article Dans Une Revue Nature Genetics Année : 2020

cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing

Gillian Rice
Duncan Sproul
Jonny Hertzog
Julien Baruteau
Ram Kumar
John Livingston
Charles Marques Lorenço
  • Fonction : Auteur
Christiaan Scott
Hélio van Der Linden
  • Fonction : Auteur
Marie Vermelle
  • Fonction : Auteur
Kate Webb
Martin Reijns
Nick Gilbert

Résumé

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.

Dates et versions

hal-03367600 , version 1 (06-10-2021)

Identifiants

Citer

Carolina Uggenti, Alice Lepelley, Marine Depp, Andrew Badrock, Mathieu P Rodero, et al.. cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing. Nature Genetics, 2020, 52 (12), pp.1364-1372. ⟨10.1038/s41588-020-00737-3⟩. ⟨hal-03367600⟩
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