Chronic endoplasmic reticulum stress in myotonic dystrophy type 2 promotes autoimmunity via mitochondrial DNA release
Nature Communications · 25 authors, 10 centres
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Using patient-derived fibroblasts and PBMCs alongside THP-1 monocyte mechanistic experiments, this study shows that chronic ATF6-mediated ER stress in DM2 drives sublethal mitochondrial DNA release into the cytoplasm, which activates cGAS/STING and a type I interferon signature associated with autoimmunity.
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This study investigates the mechanism linking myotonic dystrophy type 2 (DM2) to autoimmunity using PBMCs, primary fibroblasts from DM2 patients, and THP-1 human monocytes for mechanistic validation. The authors demonstrate that RNA-repeat accumulation in DM2 fibroblasts triggers RAN translation of tetrapeptide expansion proteins, leading to chronic activation of the ATF6 branch of the unfolded protein response. This chronic ER stress promotes sublethal mitochondrial DNA release into the cytoplasm, where it activates the cGAS/STING DNA sensing pathway, resulting in a type I interferon gene signature. The prevalence of antinuclear antibodies was 76% in DM2 patients compared to 36% in healthy controls. Depletion of mtDNA abrogated the ISG response in both THP-1 cells and fibroblasts, confirming mtDNA as the upstream trigger.
