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.

cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing / C. Uggenti, A. Lepelley, M. Depp, A.P. Badrock, M.P. Rodero, M.-. El-Daher, G.I. Rice, S. Dhir, A.P. Wheeler, A. Dhir, W. Albawardi, M.-. Fremond, L. Seabra, J. Doig, N. Blair, M.J. Martin-Niclos, E. Della Mina, A. Rubio-Roldan, J.L. Garcia-Perez, D. Sproul, J. Rehwinkel, J. Hertzog, A. Boland-Auge, R. Olaso, J.-. Deleuze, J. Baruteau, K. Brochard, J. Buckley, V. Cavallera, C. Cereda, L.M.H. De Waele, A. Dobbie, D. Doummar, F. Elmslie, M. Koch-Hogrebe, R. Kumar, K. Lamb, J.H. Livingston, A. Majumdar, C.M. Lorenco, S. Orcesi, S. Peudenier, K. Rostasy, C.A. Salmon, C. Scott, D. Tonduti, G. Touati, M. Valente, H. van der Linden, H. Van Esch, M. Vermelle, K. Webb, A.P. Jackson, M.A.M. Reijns, N. Gilbert, Y.J. Crow. - In: NATURE GENETICS. - ISSN 1061-4036. - 52:12(2020 Dec), pp. 1364-1372. [10.1038/s41588-020-00737-3]

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

D. Tonduti;
2020

Abstract

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.
Settore MED/39 - Neuropsichiatria Infantile
dic-2020
Article (author)
File in questo prodotto:
File Dimensione Formato  
2021 ags8 e ags9.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 10.12 MB
Formato Adobe PDF
10.12 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/938736
Citazioni
  • ???jsp.display-item.citation.pmc??? 57
  • Scopus 103
  • ???jsp.display-item.citation.isi??? 100
social impact