ArticleNature communications2024
Chronic endoplasmic reticulum stress in myotonic dystrophy type 2 promotes autoimmunity via mitochondrial DNA release.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 11 citations in OpenAlex.
- An Ultrastructural and Proteomic Analysis in DM1 Young Adults' Myoblasts: Stressed RER and Mitochondrial Dysfunction Involvement.Journal of cellular and molecular medicine · 2026Article
- Current biomarker development in myotonic dystrophies.Journal of neurology · 2026Review
- Distinct cellular effects of myotonic dystrophy type 2 repeat-associated non-AUG tetrapeptides.Disease models & mechanisms · 2026Article
- Convergent innate immune and regulated cell-death pathways in selected myopathies.Frontiers in immunology · 2026Review
- IgG4-Related Disease Associated With Myotonic Dystrophy Type 2.European journal of neurology · 2025Article
- cGAS, an innate dsDNA sensor with multifaceted functions.Cell insight · 2025Review
- Targeting ATF6α Attenuates UVB-Induced Senescence and Improves Skin Homeostasis by Regulating IL8 Expression.Aging cell · 2025Article
- Myotonic dystrophies: an update on clinical features, molecular mechanisms, management, and gene therapy.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Review
- Review
- The cGAS-STING/PERK-eIF2α: Individual or Potentially Collaborative Signaling Transduction in Cardiovascular Diseases.International journal of biological sciences · 2024Review
- DNA sensing of dendritic cells in cancer immunotherapy.Frontiers in molecular biosciences · 2024Review
Corrections and comments
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Authors and funding
25 authors at 6 institutions in 2 countries.
Funding
Abstract
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.
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Registered trials
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