IRGM1 links mitochondrial quality control to autoimmunity

• Published in: Nature immunology Vol. 22; no. 3; pp. 312 - 321
• Main Authors: Rai, Prashant, Janardhan, Kyathanahalli S., Meacham, Julie, Madenspacher, Jennifer H., Lin, Wan-Chi, Karmaus, Peer W. F., Martinez, Jennifer, Li, Quan-Zhen, Yan, Mei, Zeng, Jialiu, Grinstaff, Mark W., Shirihai, Orian S., Taylor, Gregory A., Fessler, Michael B.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2021; Nature Publishing Group
• Subjects: 631/250/127; 631/250/262; 631/250/38; 631/80/39; 692/420/2780; AMP; Animals; Autoimmune diseases; Autoimmune Diseases - genetics; Autoimmune Diseases - immunology; Autoimmune Diseases - metabolism; Autoimmune Diseases - pathology; Autoimmunity; Autophagy; Biomedical and Life Sciences; Biomedicine; Care and treatment; Cells, Cultured; Cyclic GMP; Cytosol; Deoxyribonucleic acid; Development and progression; DNA; Enzymes; Fibroblasts; Fibroblasts - immunology; Fibroblasts - metabolism; Fibroblasts - pathology; Gene Expression Regulation; Genetic aspects; GTP-Binding Proteins - deficiency; GTP-Binding Proteins - genetics; GTP-Binding Proteins - metabolism; Health aspects; Hydrolases; Immunology; Infectious Diseases; Inflammation; Inflammatory diseases; Lacrimal gland and Nasolacrimal duct; Macrophages; Macrophages - immunology; Macrophages - metabolism; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mitochondria - genetics; Mitochondria - immunology; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial DNA; Mitophagy; Nucleic acids; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; Pancreas; Pathology; Phagocytosis; Quality control; Signal Transduction; Toll-Like Receptor 7 - genetics; Toll-Like Receptor 7 - metabolism; Toll-like receptors; γ-Interferon; United States
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-020-00859-0

Mitochondrial abnormalities have been noted in lupus, but the causes and consequences remain obscure. Autophagy-related genes ATG5 , ATG7 and IRGM have been previously implicated in autoimmune disease. We reasoned that failure to clear defective mitochondria via mitophagy might be a foundational driver in autoimmunity by licensing mitochondrial DNA–dependent induction of type I interferon. Here, we show that mice lacking the GTPase IRGM1 (IRGM homolog) exhibited a type I interferonopathy with autoimmune features. Irgm1 deletion impaired the execution of mitophagy with cell-specific consequences. In fibroblasts, mitochondrial DNA soiling of the cytosol induced cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING)-dependent type I interferon, whereas in macrophages, lysosomal Toll-like receptor 7 was activated. In vivo, Irgm1 –/– tissues exhibited mosaic dependency upon nucleic acid receptors. Whereas salivary and lacrimal gland autoimmune pathology was abolished and lung pathology was attenuated by cGAS and STING deletion, pancreatic pathology remained unchanged. These findings reveal fundamental connections between mitochondrial quality control and tissue-selective autoimmune disease. Fessler and colleagues report that loss of the IFN-γ-induced GTPase IRGM1 results in autoinflammatory disease. Deficient IRGM1 activity led to defective lysosomal maturation and impaired mitophagy, prompting the release of cytosolic mtDNA and thereby activating the cGAS–STING pathway.