| Title: |
Heterozygous RELA mutations cause early-onset systemic lupus erythematosus by hijacking the NF-κB pathway towards transcriptional activation of type-I Interferon genes |
| Authors: |
Barnabei, Laura; Lamrini, Hicham; Castela, Mathieu; Jeremiah, Nadia; Stolzenberg, Marie-Claude; Chentout, Loïc; Jacques, Sidonie; Bouafia, Amine; Magérus-Chatinet, Aude; Moncan, Matthieu; Mirshahvalad, Sajedeh; Pellé, Olivier; Bondet, Vincent; Duffy, Darragh; Parisot, Mélanie; Bras, Marc; Uggenti, Carolina; Salomon, Rémi; Bodemer, Christine; Rabant, Marion; Cavazzana, Marina; Miner, J.J.; Belot, Alexandre; Hié, Miguel; Picard, Capucine; Bader-Meunier, Brigitte; Kracker, Sven; Rieux-Laucat, Frédéric |
| Contributors: |
Imagine - Institut des maladies génétiques (IMAGINE - U1163); Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM); Centre de Recherche Saint-Antoine (UMRS893); Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM); Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163); Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM); Developpement Normal et Pathologique du Système Immunitaire; Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Immunobiologie des Cellules dendritiques; Institut Pasteur Paris (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| Source: |
https://hal.science/hal-03001914 ; 2020. |
| Publisher Information: |
CCSD |
| Publication Year: |
2020 |
| Subject Terms: |
[SDV]Life Sciences [q-bio] |
| Description: |
Systemic Lupus Erythematosus (SLE) is an autoimmune and inflammatory disease characterized by uncontrolled production of autoantibodies and inflammatory cytokines such as the type-I interferons. Due to the lack of precise pathophysiological mechanisms, treatments are based on broad unspecific immunossupression. To identify genetic factors associated with SLE we performed whole exome sequencing and identified two RELA heterozygous activating mutations in 3 early-onset and familial SLE cases. The corresponding RELA/p65 mutant were abundant in the nucleus but poorly activate transcription of genes controlled by NF-κB consensus sequences. The co-expression of the mutant and wild-type RELA/p65 strongly activated the expression of genes controlled by the IFNα-consensus sequences. These molecular mechanisms lead to the overproduction of type-I IFN in the patients’ cells. Our findings highlight a novel mechanism of autoimmunity where these new RELA mutants are transactivating the type-I IFN genes and are thus promoting type-I interferon production and early-onset SLE, thereby paving the way to the identification of new and specific therapeutic targets. |
| Document Type: |
report |
| Language: |
English |
| DOI: |
10.1101/2020.04.27.046102 |
| Availability: |
https://hal.science/hal-03001914; https://doi.org/10.1101/2020.04.27.046102 |
| Accession Number: |
edsbas.BC2AE63B |
| Database: |
BASE |