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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This study shows that myotonic dystrophy type 2 (DM2) patients have a high prevalence of autoimmune diseases (40.5%) and elevated type I interferon (IFN) signatures. The mechanism involves chronic ER stress via the ATF6 pathway, leading to mitochondrial DNA leakage into the cytoplasm, which activates the cGAS/STING pathway and drives IFN production. These findings identify potential therapeutic targets for autoimmunity in repeat expansion diseases.

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**Background:** Myotonic dystrophy type 2 (DM2) is a tetranucleotide CCTG repeat expansion disease associated with an increased prevalence of autoimmunity. The mechanism linking repeat expansions to autoimmunity was unknown. This study aimed to investigate the role of type I interferon (IFN) signaling and the underlying molecular pathway in DM2-associated autoimmunity.

**Methods:** The study included 37 DM2 patients, 13 DM1 patients, and healthy controls. Autoimmune disease prevalence and antinuclear antibodies (ANA) were assessed. Type I IFN-stimulated gene (ISG) expression was measured in blood, skin biopsies, and cultured fibroblasts using RT-PCR and RNA sequencing. Fibroblasts from 7 DM2, 4 DM1, and 5 healthy controls were analyzed. RNA fluorescence in situ hybridization (FISH) detected CCUG repeat accumulation. siRNA knockdowns, CRISPR/Cas9 gene editing in THP-1 cells, and pharmacological inhibitors were used to dissect signaling pathways. Mitochondrial DNA (mtDNA) release was measured by subcellular fractionation and PCR. ER stress was induced with thapsigargin (TG), tunicamycin (TN), cyclopiazonic acid (CPA), and BHQ.

**Key Results:** Autoimmune diseases were present in 40.5% of DM2 patients (vs. 5-10% in general population). ANA positivity was 75.7% in DM2 and 61.5% in DM1 (vs. 36% in controls). An elevated ISG signature was found in blood and fibroblasts of DM2 patients, with higher expression than DM1 (two-way ANOVA p=0.0004). RNA repeats accumulated in both nucleus and cytoplasm of DM2 fibroblasts. Knockdown of RNA sensors (RIG-I, MDA5, MAVS, TLR3) did not reduce ISG expression. DM2 fibroblasts showed chronic ER stress with increased BiP mRNA, PERK protein, and cleaved ATF6-N, but reduced IRE1α. siRNA knockdown of ATF6 reduced ISG levels to control levels. In THP-1 cells, ER stress induced CXCL10 release dependent on cGAS, STING, IRF3, and ATF6, but not MAVS, PERK, or IRE1α. mtDNA depletion with IMT1 or ddC abrogated ISG induction. DM2 fibroblasts had elevated cytosolic mtDNA (p<0.05) and mitochondrial ROS, but normal total mtDNA and oxygen consumption rate. cGAS or STING knockdown reduced ISG expression in DM2 fibroblasts.

**Clinical Implications:** This study reveals a novel mechanism linking chronic ER stress, mtDNA release, and cGAS/STING-dependent type I IFN activation in DM2, explaining the increased autoimmunity risk. The findings suggest that targeting the ATF6 pathway, cGAS/STING, or type I IFN signaling (e.g., with JAK inhibitors or IFNAR blockers) could be therapeutic strategies for DM2-associated autoimmune manifestations. This pathway may also be relevant to other repeat expansion diseases and conditions with chronic ER stress.

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other

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neurology

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88% · B

ORIGINAL PAPER

PMC10879130

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

Nature Communications

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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.

CITATION EXPORT

Sarah Rösing, Fabian Ullrich, Susann Meisterfeld et al.. Chronic endoplasmic reticulum stress in myotonic dystrophy type 2 promotes autoimmunity via mitochondrial DNA release. Nature Communications. (2024). https://doi.org/10.1038/s41467-024-45535-1

AUTHORS

25 · 10 CENTRES

Sarah Rösing, Fabian Ullrich, Susann Meisterfeld, Franziska Schmidt, Laura Mlitzko, Marijana Croon, Ryan G Nattrass, Nadia Eberl, Julia Mahlberg, Martin Schlee, Anja Wieland, Philipp Simon, Daniel Hilbig, Ulrike Reuner, Alexander Rapp, Julia Bremser, Peter Mirtschink, Stephan Drukewitz, Thomas Zillinger, Stefan Beissert, Katrin Paeschke, Gunther Hartmann, Aleksandra Trifunovic, Eva Bartok, Claudia Günther

1https://ror.org/04za5zm41grid.412282.f0000 0001 1091 2917Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
2https://ror.org/01xnwqx93grid.15090.3d0000 0000 8786 803XInstitute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53127 Bonn, Germany
3https://ror.org/01xnwqx93grid.15090.3d0000 0000 8786 803XInstitute of Experimental Haematology and Transfusion Medicine, University Hospital Bonn, 53127 Bonn, Germany
4grid.452408.fInstitute for Mitochondrial Diseases and Aging, Faculty of Medicine, CECAD Research Center, 50931 Cologne, Germany
5https://ror.org/01xnwqx93grid.15090.3d0000 0000 8786 803XDepartment of Oncology, Hematology, Rheumatology and Immune-Oncology, University Hospital Bonn, 53127 Bonn, Germany
6https://ror.org/04za5zm41grid.412282.f0000 0001 1091 2917Department of Neurology, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
7https://ror.org/05n911h24grid.6546.10000 0001 0940 1669Department of Biology, Cell biology and Epigenetic, Technical University of Darmstadt, Darmstadt, Germany
8Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, TU Dresden, 01307 Dresden, Germany
9grid.9647.c0000 0004 7669 9786Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), Partner Site Dresden, Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
10grid.11505.300000 0001 2153 5088Unit of Experimental Immunology, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium