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IRGM1 links mitochondrial quality control to autoimmunity
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 dri...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906953/ https://www.ncbi.nlm.nih.gov/pubmed/33510463 http://dx.doi.org/10.1038/s41590-020-00859-0 |
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author | 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. |
author_facet | 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. |
author_sort | Rai, Prashant |
collection | PubMed |
description | 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 (mt)DNA-dependent induction of type I interferon (IFN-I). Here, we show that mice lacking the GTPase IRGM1 (IRGM homologue) exhibited a type I interferonopathy with autoimmune features. Irgm1 deletion impaired execution of mitophagy with cell-specific consequences. In fibroblasts, mtDNA soiling of the cytosol induced cyclic GMP-AMP synthase (cGAS)–Stimulator of Interferon Genes (STING)-dependent IFN-I, whereas in macrophages, lysosomal TLR7 was activated. In vivo, Irgm1(−/−) tissues exhibited mosaic dependency upon nucleic acid receptors. Whereas salivary and lacrimal gland autoimmune pathology were 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. |
format | Online Article Text |
id | pubmed-7906953 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
record_format | MEDLINE/PubMed |
spelling | pubmed-79069532021-07-28 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. Nat Immunol Article 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 (mt)DNA-dependent induction of type I interferon (IFN-I). Here, we show that mice lacking the GTPase IRGM1 (IRGM homologue) exhibited a type I interferonopathy with autoimmune features. Irgm1 deletion impaired execution of mitophagy with cell-specific consequences. In fibroblasts, mtDNA soiling of the cytosol induced cyclic GMP-AMP synthase (cGAS)–Stimulator of Interferon Genes (STING)-dependent IFN-I, whereas in macrophages, lysosomal TLR7 was activated. In vivo, Irgm1(−/−) tissues exhibited mosaic dependency upon nucleic acid receptors. Whereas salivary and lacrimal gland autoimmune pathology were 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. 2021-01-28 2021-03 /pmc/articles/PMC7906953/ /pubmed/33510463 http://dx.doi.org/10.1038/s41590-020-00859-0 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article 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. IRGM1 links mitochondrial quality control to autoimmunity |
title | IRGM1 links mitochondrial quality control to autoimmunity |
title_full | IRGM1 links mitochondrial quality control to autoimmunity |
title_fullStr | IRGM1 links mitochondrial quality control to autoimmunity |
title_full_unstemmed | IRGM1 links mitochondrial quality control to autoimmunity |
title_short | IRGM1 links mitochondrial quality control to autoimmunity |
title_sort | irgm1 links mitochondrial quality control to autoimmunity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906953/ https://www.ncbi.nlm.nih.gov/pubmed/33510463 http://dx.doi.org/10.1038/s41590-020-00859-0 |
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