IRGM1, a guardian of mitochondrial DAMP-mediated autoinflammation

Abstract

IRGM1 is recognized as a master regulator of type I interferon responses against pathogens, while also protecting against autoimmune diseases. It has now been shown that IRGM1 controls autoinflammatory responses by modulating mitophagy flux.

Fig. 1 |. Irgm1 controls mitochondrial DamP signaling and IFN-I activation through distinct pathways in somatic and immune cells.

In the presence of IRGM1, damaged and IFN-γ-stressed mitochondria are removed by mitophagy, protecting against mitochondrial DAMP–induced interferonopathy and autoinflammatory responses. IRGM1 deficiency in fibroblasts promotes lysosome dysfunction, allowing the cytoplasmic activation of the cGAS–STING pathway by cytosolic mtDNA. By contrast, in bone-marrow-derived macrophages, IRGM1 promotes autophagosome–lysosome fusion to suppress the activation of endosomal TLR7 by mitochondrial DAMPs.