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

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 and Claudia Günther ()
Additional contact information
Sarah Rösing: University Hospital Carl Gustav Carus
Fabian Ullrich: University Hospital Bonn
Susann Meisterfeld: University Hospital Carl Gustav Carus
Franziska Schmidt: University Hospital Carl Gustav Carus
Laura Mlitzko: University Hospital Carl Gustav Carus
Marijana Croon: CECAD Research Center
Ryan G Nattrass: University Hospital Bonn
Nadia Eberl: University Hospital Carl Gustav Carus
Julia Mahlberg: University Hospital Bonn
Martin Schlee: University Hospital Bonn
Anja Wieland: University Hospital Bonn
Philipp Simon: University Hospital Bonn
Daniel Hilbig: University Hospital Bonn
Ulrike Reuner: University Hospital Carl Gustav Carus
Alexander Rapp: Technical University of Darmstadt
Julia Bremser: University Hospital Bonn
Peter Mirtschink: Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine
Stephan Drukewitz: University of Leipzig Medical Center
Thomas Zillinger: University Hospital Bonn
Stefan Beissert: University Hospital Carl Gustav Carus
Katrin Paeschke: University Hospital Bonn
Gunther Hartmann: University Hospital Bonn
Aleksandra Trifunovic: CECAD Research Center
Eva Bartok: University Hospital Bonn
Claudia Günther: University Hospital Carl Gustav Carus

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45535-1

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