Autoimmunity geneIRGMsuppressescGAS-STINGandRIG-I-MAVSsignaling to control interferon response

Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases. Loss of function of Immunity Related GTPase M (IRGM) has also been associated to several autoimmune diseases, but its mechanism of action is unknown. Here, we found thatIRGMis a master negative regulator of the interferon response. Several nucleic acid-sensing pathways leading to interferon-stimulated gene expression are highly activated inIRGMknockout mice and human cells. Mechanistically, we show thatIRGMinteracts with nucleic acid sensor proteins, includingcGASandRIG-I, and mediates their p62-dependent autophagic degradation to restrain interferon signaling. Further,IRGMdeficiency results in defective mitophagy leading to the accumulation of defunct leaky mitochondria that release cytosolicDAMPs and mtROS. Hence,IRGMdeficiency increases not only the levels of the sensors, but also those of the stimuli that trigger the activation of thecGAS-STINGandRIG-I-MAVSsignaling axes, leading to robust induction ofIFNresponses. Taken together, this study defines the molecular mechanisms by whichIRGMmaintains interferon homeostasis and protects from autoimmune diseases.