Chronic ER stress promotes cGAS/mtDNA-induced autoimmunity via ATF6 in myotonic dystrophy type 2

Myotonic dystrophy type 2 (DM2) results from large CCTG repeats in the CNBP gene leading to myopathy and an increased prevalence of autoimmunity. Therefore, the potential innate immune response to nucleic-acid accumulation during DM2 was scrutinized. Interestingly, DM2 patients exhibited a 15-fold induced type-I interferon (IFN) signature in blood (p=0.007) and 7-fold induced IFN signature in cultured fibroblasts (p=0.03). Moreover, RNA repeat accumulation was prevalent in the cytosol of DM2 patient fibroblasts. However, activation of innate immune RNA sensors was not induced. Instead, repeat-associated non-AUG translation lead to an accumulation of the non-sense protein LPAC in DM2 fibroblasts. The aforementioned factors induce chronic endoplasmic reticulum (ER) stress, characterized by altered expression of pancreatic ER kinase (PKR)-like ER kinase (PERK), and inositol requiring enzyme 1 (IRE1) and activation of the activating transcription factor 6 (ATF6) pathway. Chronic ER stress has been associated with mitochondrial stress and cytosolic leakage of mtDNA in DM2 patient fibroblasts leading to cGAS/STING dependent type-I IFN induction. Altogether, these findings demonstrate a novel mechanism by which large repeat expansions induce a type-I IFN response predisposing DM2 patients to autoimmunity.