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Enhanced cGAS-STING–dependent interferon signaling associated with mutations in ATAD3A
Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features sug...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374862/ https://www.ncbi.nlm.nih.gov/pubmed/34387651 http://dx.doi.org/10.1084/jem.20201560 |
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author | Lepelley, Alice Della Mina, Erika Van Nieuwenhove, Erika Waumans, Lise Fraitag, Sylvie Rice, Gillian I. Dhir, Ashish Frémond, Marie-Louise Rodero, Mathieu P. Seabra, Luis Carter, Edwin Bodemer, Christine Buhas, Daniela Callewaert, Bert de Lonlay, Pascale De Somer, Lien Dyment, David A. Faes, Fran Grove, Lucy Holden, Simon Hully, Marie Kurian, Manju A. McMillan, Hugh J. Suetens, Kristin Tyynismaa, Henna Chhun, Stéphanie Wai, Timothy Wouters, Carine Bader-Meunier, Brigitte Crow, Yanick J. |
author_facet | Lepelley, Alice Della Mina, Erika Van Nieuwenhove, Erika Waumans, Lise Fraitag, Sylvie Rice, Gillian I. Dhir, Ashish Frémond, Marie-Louise Rodero, Mathieu P. Seabra, Luis Carter, Edwin Bodemer, Christine Buhas, Daniela Callewaert, Bert de Lonlay, Pascale De Somer, Lien Dyment, David A. Faes, Fran Grove, Lucy Holden, Simon Hully, Marie Kurian, Manju A. McMillan, Hugh J. Suetens, Kristin Tyynismaa, Henna Chhun, Stéphanie Wai, Timothy Wouters, Carine Bader-Meunier, Brigitte Crow, Yanick J. |
author_sort | Lepelley, Alice |
collection | PubMed |
description | Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain–containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A and recorded up-regulated ISG expression and interferon α protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy. |
format | Online Article Text |
id | pubmed-8374862 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-83748622022-04-04 Enhanced cGAS-STING–dependent interferon signaling associated with mutations in ATAD3A Lepelley, Alice Della Mina, Erika Van Nieuwenhove, Erika Waumans, Lise Fraitag, Sylvie Rice, Gillian I. Dhir, Ashish Frémond, Marie-Louise Rodero, Mathieu P. Seabra, Luis Carter, Edwin Bodemer, Christine Buhas, Daniela Callewaert, Bert de Lonlay, Pascale De Somer, Lien Dyment, David A. Faes, Fran Grove, Lucy Holden, Simon Hully, Marie Kurian, Manju A. McMillan, Hugh J. Suetens, Kristin Tyynismaa, Henna Chhun, Stéphanie Wai, Timothy Wouters, Carine Bader-Meunier, Brigitte Crow, Yanick J. J Exp Med Brief Definitive Report Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain–containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A and recorded up-regulated ISG expression and interferon α protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy. Rockefeller University Press 2021-08-13 /pmc/articles/PMC8374862/ /pubmed/34387651 http://dx.doi.org/10.1084/jem.20201560 Text en © 2021 Lepelley et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Brief Definitive Report Lepelley, Alice Della Mina, Erika Van Nieuwenhove, Erika Waumans, Lise Fraitag, Sylvie Rice, Gillian I. Dhir, Ashish Frémond, Marie-Louise Rodero, Mathieu P. Seabra, Luis Carter, Edwin Bodemer, Christine Buhas, Daniela Callewaert, Bert de Lonlay, Pascale De Somer, Lien Dyment, David A. Faes, Fran Grove, Lucy Holden, Simon Hully, Marie Kurian, Manju A. McMillan, Hugh J. Suetens, Kristin Tyynismaa, Henna Chhun, Stéphanie Wai, Timothy Wouters, Carine Bader-Meunier, Brigitte Crow, Yanick J. Enhanced cGAS-STING–dependent interferon signaling associated with mutations in ATAD3A |
title | Enhanced cGAS-STING–dependent interferon signaling associated with mutations in ATAD3A |
title_full | Enhanced cGAS-STING–dependent interferon signaling associated with mutations in ATAD3A |
title_fullStr | Enhanced cGAS-STING–dependent interferon signaling associated with mutations in ATAD3A |
title_full_unstemmed | Enhanced cGAS-STING–dependent interferon signaling associated with mutations in ATAD3A |
title_short | Enhanced cGAS-STING–dependent interferon signaling associated with mutations in ATAD3A |
title_sort | enhanced cgas-sting–dependent interferon signaling associated with mutations in atad3a |
topic | Brief Definitive Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374862/ https://www.ncbi.nlm.nih.gov/pubmed/34387651 http://dx.doi.org/10.1084/jem.20201560 |
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