Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden, 01307, Dresden, Germany.
Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53127, Bonn, Germany.
Nat Commun. 2024 Feb 20;15(1):1534. doi: 10.1038/s41467-024-45535-1.
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.
肌强直性营养不良 2 型（DM2）是一种四核苷酸 CCTG 重复扩展疾病，与自身免疫的患病率增加有关。在这里，我们在 DM2 患者的外周血单核细胞和原代成纤维细胞中鉴定出一种升高的 I 型干扰素（IFN）特征，作为慢性免疫刺激的触发因素。尽管 RNA 重复积累普遍存在于 DM2 患者成纤维细胞的细胞质中，但 I 型 IFN 的释放并不依赖于先天 RNA 免疫传感器，而是依赖于 DNA 传感器 cGAS 和细胞质中线粒体 DNA（mtDNA）的普遍性。亚致死 mtDNA 的释放是由未折叠蛋白反应（UPR）的 ATF6 分支的慢性激活引起的，该分支反应是针对 RNA 重复积累和非 AUG 翻译的四肽扩展蛋白。在人类 THP-1 单核细胞中，也可以在慢性内质网（ER）应激下重现 ATF6 依赖性 mtDNA 释放和由此产生的 cGAS/STING 激活。总之，我们的研究表明，大的重复扩展导致慢性内质网应激和相关 mtDNA 渗漏的新机制。这种 mtDNA 反过来又被 cGAS/STING 途径感知，并诱导 I 型 IFN 反应，易患自身免疫。阐明这条途径为与重复扩展疾病相关的自身免疫性疾病揭示了新的潜在治疗靶点。
