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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.
Afiliación
  • Rai P; Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA. prashant.rai@nih.gov.
  • Janardhan KS; Cellular & Molecular Pathology Branch, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
  • Meacham J; Integrated Laboratory Systems, Inc., Research Triangle Park, NC, USA.
  • Madenspacher JH; Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
  • Lin WC; Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
  • Karmaus PWF; Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
  • Martinez J; Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
  • Li QZ; Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
  • Yan M; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Zeng J; Microarray Core Facility, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Grinstaff MW; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Shirihai OS; Microarray Core Facility, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Taylor GA; Department of Biomedical Engineering, Boston University, Boston, MA, USA.
  • Fessler MB; Department of Biomedical Engineering, Boston University, Boston, MA, USA.
Nat Immunol ; 22(3): 312-321, 2021 03.
Article en En | MEDLINE | ID: mdl-33510463
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Autoinmunes / Autoinmunidad / Proteínas de Unión al GTP / Fibroblastos / Mitofagia / Mitocondrias Límite: Animals Idioma: En Revista: Nat Immunol Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Autoinmunes / Autoinmunidad / Proteínas de Unión al GTP / Fibroblastos / Mitofagia / Mitocondrias Límite: Animals Idioma: En Revista: Nat Immunol Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos