Heterozygous RELA mutations cause early-onset systemic lupus erythematosus by hijacking the NF-κB pathway towards transcriptional activation of type-I Interferon genes - Université Paris Cité Accéder directement au contenu
Pré-Publication, Document De Travail Année : 2020

Heterozygous RELA mutations cause early-onset systemic lupus erythematosus by hijacking the NF-κB pathway towards transcriptional activation of type-I Interferon genes

Amine Bouafia
  • Fonction : Auteur
  • PersonId : 772314
  • IdRef : 185045669
Matthieu Moncan
  • Fonction : Auteur
Sajedeh Mirshahvalad
  • Fonction : Auteur
Olivier Pellé
  • Fonction : Auteur
Darragh Duffy
Mélanie Parisot
Marc Bras
  • Fonction : Auteur
Carolina Uggenti
  • Fonction : Auteur
Rémi Salomon
  • Fonction : Auteur
Christine Bodemer
Marion Rabant
Marina Cavazzana
J.J. Miner
  • Fonction : Auteur
Alexandre Belot
Miguel Hié
  • Fonction : Auteur
Capucine Picard
Brigitte Bader-Meunier
Sven Kracker
Frédéric Rieux-Laucat
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-03001914 , version 1 (12-11-2020)

Identifiants

Citer

Laura Barnabei, Hicham Lamrini, Mathieu Castela, Nadia Jeremiah, Marie-Claude Stolzenberg, et al.. Heterozygous RELA mutations cause early-onset systemic lupus erythematosus by hijacking the NF-κB pathway towards transcriptional activation of type-I Interferon genes. 2020. ⟨hal-03001914⟩
61 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More