4 research outputs found
IRGM restrains NLRP3 inflammasome activation by mediating its SQSTM1/p62-dependent selective autophagy
TRIM16 governs the biogenesis and disposal of stress-induced protein aggregates to evade cytotoxicity: implication for neurodegeneration and cancer
Autoimmunity gene IRGM suppresses cGAS-STING and RIG-I-MAVS signaling 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 that IRGM is a master negative regulator of the interferon response. Several nucleic acidāsensing pathways leading to interferonāstimulated gene expression are highly activated in IRGM knockout mice and human cells. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIGāI, and mediates their p62ādependent autophagic degradation to restrain interferon signaling. Further, IRGM deficiency results in defective mitophagy leading to the accumulation of defunct leaky mitochondria that release cytosolic DAMPs and mtROS. Hence, IRGM deficiency increases not only the levels of the sensors, but also those of the stimuli that trigger the activation of the cGASāSTING and RIGāIāMAVS signaling axes, leading to robust induction of IFN responses. Taken together, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases