cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing
Open accessAbstract
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.
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cGAS is regulated by chromatin structure.
“chromatin structure (Uggenti et al., 2020)”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Uggenti et al., 2020
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References 51 · Cited by 192
- Authors
- Uggenti, C., Lepelley, A., Depp, M., Badrock, A. P., Rodero, M. P., El-Daher, M.-T., Rice, G. I., Dhir, S., Wheeler, A. P., Dhir, A., Albawardi, W., Frémond, M.-L., Seabra, L., Doig, J., Blair, N., Martin-Niclos, M. J., Della Mina, E., Rubio-Roldán, A., García-Pérez, J. L., Sproul, D., Rehwinkel, J., Hertzog, J., Boland-Auge, A., Olaso, R., Deleuze, J.-F., Baruteau, J., Brochard, K., Buckley, J., Cavallera, V., Cereda, C., De Waele, L. M. H., Dobbie, A., Doummar, D., Elmslie, F., Koch-Hogrebe, M., Kumar, R., Lamb, K., Livingston, J. H., Majumdar, A., Lorenço, C. M., Orcesi, S., Peudenier, S., Rostasy, K., Salmon, C. A., Scott, C., Tonduti, D., Touati, G., Valente, M., van der Linden, H., Van Esch, H., Vermelle, M., Webb, K., Jackson, A. P., Reijns, M. A. M., Gilbert, N., & Crow, Y. J.
- Affiliations
- Institute of Genetics and Cancer (GB)
- Université Paris Cité (FR)
- Manchester Academic Health Science Centre (GB)
- Universidad de Granada (ES)
- Edinburgh Cancer Research (GB)
- University of Oxford (GB)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- University College London (GB)
- Centre Hospitalier Universitaire de Toulouse (FR)
- University of Cape Town (ZA)
- Fondazione Istituto Neurologico Nazionale Casimiro Mondino (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Chapel Allerton Hospital (GB)
- Sorbonne Université (FR)
- University of London (GB)
- National Health Service (GB)
- Gloucestershire Royal Hospital (GB)
- Bristol Royal Hospital for Children (GB)
- University of Pavia (IT)
- Centre Hospitalier Régional Universitaire de Brest (FR)
- Witten/Herdecke University (DE)
- Royal Surrey County Hospital (GB)
- Ospedale dei Bambini Vittore Buzzi (IT)
- Corresponding author
- Crow, Yanick J.
- ORCID
- Uggenti, Carolina
- Lepelley, Alice
- Depp, Marine
- Badrock, Andrew P.
- Rodero, Mathieu P.
- Rice, Gillian I.
- Dhir, Somdutta
- Wheeler, Ann P.
- Dhir, Ashish
- Frémond, Marie-Louise
- Seabra, Luis
- Doig, Jennifer
- Blair, Natalie
- Della Mina, Erika
- Rubio-Roldán, Alejandro
- García-Pérez, Jose L.
- Sproul, Duncan
- Rehwinkel, Jan
- Hertzog, Jonny
- Boland-Auge, Anne
- Olaso, Robert
- Deleuze, Jean-François
- Baruteau, Julien
- Buckley, Jonathan
- Cavallera, Vanessa
- Cereda, Cristina
- Doummar, Diane
- Elmslie, Frances
- Kumar, Ram
- Livingston, John H.
- Majumdar, Anirban
- Orcesi, Simona
- Peudenier, Sylviane
- Rostasy, Kevin
- Scott, Christiaan
- Tonduti, Davide
- Valente, Marialuisa
- Vermelle, Marie
- Webb, Kate
- Reijns, Martin A. M.
- Gilbert, Nick
- Crow, Yanick J.
- Venue
- Nature Genetics
- Published
- 2020-11-23
- Volume
- 52
- Issue
- 12
- Pages
- 1364-1372
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W3108977719
- Cited by
- 192
- References
- 51
- Citations by year
- 2026: 24 · 2025: 39 · 2024: 27 · 2023: 33 · 2022: 30 · 2021: 38 · 2020: 1
- FWCI
- 8.93
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, other-oa)
- HAL (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion, other-oa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Explore Bristol Research (submittedVersion)
- Funders
- Wellcome Trust (Z/17/Z, 208345/Z/17/Z)
- Francis Crick Institute (10647)
- Cancer Research UK (20837, C47648/A20837)
- National Institute for Health and Care Research
- European Commission (HORIZON2020)
- Agence Nationale de la Recherche (ANR-10-INBS-0009, ANR-10-IAHU- 01, 10-IAHU-01, ANR-10)
- Medical Research Council (MC_UU_00008/8, U127580972, MC_UU_00007/5, MC_UU_00007/13)
- MSDAVENIR
- FP7 Ideas: European Research Council (309449)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Keywords
- Aicardi-Goutières syndrome, type I interferonopathy, cGAS-STING pathway, autoinflammation, cGAMP, chromatin, fibroblasts
- MeSH terms
- STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Cell Line, Chromatin, DNA, Gene Expression Regulation, Histones, Humans, Interferon Type I, Membrane Proteins, Nervous System Malformations, Nucleotides, Cyclic, Nucleotidyltransferases, RNA Precursors, RNA-Binding Proteins, Autoimmune Diseases of the Nervous System, Ribonucleoprotein, U7 Small Nuclear, HCT116 Cells, Hereditary Autoinflammatory Diseases, HEK293 Cells
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