@article{11c6c3dacdf24f5c99f5d85eb7f916b9,
title = "IRGM1 links mitochondrial quality control to autoimmunity",
abstract = "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.",
author = "Prashant Rai and Janardhan, {Kyathanahalli S.} and Julie Meacham and Madenspacher, {Jennifer H.} and Lin, {Wan Chi} and Karmaus, {Peer W.F.} and Jennifer Martinez and Li, {Quan Zhen} and Mei Yan and Jialiu Zeng and Grinstaff, {Mark W.} and Shirihai, {Orian S.} and Taylor, {Gregory A.} and Fessler, {Michael B.}",
note = "Funding Information: We thank P. West, D. Sliter, F. Zhao, and J. Santos for helpful discussions; N. Yan (UTSW) and R. Youle (NINDS/NIH) for reagents; G. Barber (University of Miami) for Tmem173–/– mice; C. Bosio (NIAID/NIH) for Tlr9–/– mice; L. Perrow for assistance with breeding; D. King for blood cell count analysis; the NIEHS Histology Core laboratory for assistance with processing, sectioning, and staining of tissues; K. Gerrish, B. Elgart and N. Clausen of the NIEHS Molecular Genomics Core; N. Martin and D. Chen of the NIEHS Viral Vector Core; C.J. Tucker, A.K. Janoshazi, and E. Scappini of the NIEHS Fluorescence Microscopy and Imaging Center; and C. Bortner and M. Sifre of the NIEHS Flow Cytometry Core Facility. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (grant no. Z01 ES102005 (M.B.F.) and grant no. ZIA ES103286 (J. Martinez)); and by grant nos. AI135398, AI145929, and AI148243 (G.A.T.); grant no. R21AG063373 (M.W.G.); and grant no. R21AG060456 (O.S.S.). Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = mar,
day = "1",
doi = "10.1038/s41590-020-00859-0",
language = "English",
volume = "22",
pages = "312--321",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "3",
}
