Chronic endoplasmic reticulum stress in myotonic dystrophy type 2 promotes autoimmunity via mitochondrial DNA release

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung



Myotonic dystrophy type 2 (DM2) is a tetranucleotide CCTG repeat expansion disease associated with an increased prevalence of autoimmunity. Here, we identified an elevated type I interferon (IFN) signature in peripheral blood mononuclear cells and primary fibroblasts of DM2 patients as a trigger of chronic immune stimulation. Although RNA-repeat accumulation was prevalent in the cytosol of DM2-patient fibroblasts, type-I IFN release did not depend on innate RNA immune sensors but rather the DNA sensor cGAS and the prevalence of mitochondrial DNA (mtDNA) in the cytoplasm. Sublethal mtDNA release was promoted by a chronic activation of the ATF6 branch of the unfolded protein response (UPR) in reaction to RNA-repeat accumulation and non-AUG translated tetrapeptide expansion proteins. ATF6-dependent mtDNA release and resulting cGAS/STING activation could also be recapitulated in human THP-1 monocytes exposed to chronic endoplasmic reticulum (ER) stress. Altogether, our study demonstrates a novel mechanism by which large repeat expansions cause chronic endoplasmic reticulum stress and associated mtDNA leakage. This mtDNA is, in turn, sensed by the cGAS/STING pathway and induces a type-I IFN response predisposing to autoimmunity. Elucidating this pathway reveals new potential therapeutic targets for autoimmune disorders associated with repeat expansion diseases.

Titel in Übersetzung
Chronischer Stress des endoplasmatischen Retikulums bei Myotoner Dystrophie Typ 2 fördert die Autoimmunität über die Freisetzung mitochondrialer DNA


FachzeitschriftNature communications
PublikationsstatusVeröffentlicht - 20 Feb. 2024

Externe IDs

PubMed 38378748
ORCID /0000-0002-4330-1861/work/156812171
ORCID /0000-0002-3772-3590/work/156813746


Ziele für nachhaltige Entwicklung


  • Autoimmunity/genetics, Nucleotidyltransferases/genetics, Endoplasmic Reticulum Stress/genetics, RNA, Humans, DNA, Mitochondrial/genetics, Autoimmune Diseases, Myotonic Dystrophy/genetics, Leukocytes, Mononuclear/metabolism, Interferon Type I