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IRGM1 links mitochondrial quality control to autoimmunity

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

Nature immunology, 2021-03, Vol.22 (3), p.312-321 [Periódico revisado por pares]

United States: Nature Publishing Group

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Título:
IRGM1 links mitochondrial quality control to autoimmunity
Autor: 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
Assuntos: AMP ; Animals ; Autoimmune diseases ; Autoimmune Diseases - genetics ; Autoimmune Diseases - immunology ; Autoimmune Diseases - metabolism ; Autoimmune Diseases - pathology ; Autoimmunity ; Autophagy ; 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 ; 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 ; 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
É parte de: Nature immunology, 2021-03, Vol.22 (3), p.312-321
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Author Contributions
P.R. designed, conducted, and analyzed experiments and contributed to the writing of the manuscript. K.S.J., J.Me., J.H.M., W.C.L., P.W.F.K., Q.-Z.L., and M.Y. all conducted analyses and contributed to the writing of the manuscript. J.Z., O.S.S., J.Ma., M.W.G., and G.A.T. provided critical reagents and contributed to the writing of the manuscript. M.B.F. designed and analyzed experiments and contributed to the writing of the manuscript.
Descrição: 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.
Editor: United States: Nature Publishing Group
Idioma: Inglês

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IRGM1 links mitochondrial quality control to autoimmunity

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

United States: Nature Publishing Group

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