Adenosine-to-inosine editing of endogenous Z-form RNA by the deaminase ADAR1 prevents spontaneous MAVS-dependent type I interferon responses

Nucleic acids are powerful triggers of innate immunity and can adopt the Z-conformation, an unusual left-handed double helix. Here, we studied the biological function(s) of Z-RNA recognition by the adenosine deaminase ADAR1, mutations in which cause Aicardi-Goutières syndrome. Adar1(mZα/mZα) mice, b...

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Autores principales: Tang, Qiannan, Rigby, Rachel E., Young, George R., Hvidt, Astrid Korning, Davis, Tanja, Tan, Tiong Kit, Bridgeman, Anne, Townsend, Alain R., Kassiotis, George, Rehwinkel, Jan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459395/
https://www.ncbi.nlm.nih.gov/pubmed/34525337
http://dx.doi.org/10.1016/j.immuni.2021.08.011
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author Tang, Qiannan
Rigby, Rachel E.
Young, George R.
Hvidt, Astrid Korning
Davis, Tanja
Tan, Tiong Kit
Bridgeman, Anne
Townsend, Alain R.
Kassiotis, George
Rehwinkel, Jan
author_facet Tang, Qiannan
Rigby, Rachel E.
Young, George R.
Hvidt, Astrid Korning
Davis, Tanja
Tan, Tiong Kit
Bridgeman, Anne
Townsend, Alain R.
Kassiotis, George
Rehwinkel, Jan
author_sort Tang, Qiannan
collection PubMed
description Nucleic acids are powerful triggers of innate immunity and can adopt the Z-conformation, an unusual left-handed double helix. Here, we studied the biological function(s) of Z-RNA recognition by the adenosine deaminase ADAR1, mutations in which cause Aicardi-Goutières syndrome. Adar1(mZα/mZα) mice, bearing two point mutations in the Z-nucleic acid binding (Zα) domain that abolish Z-RNA binding, displayed spontaneous induction of type I interferons (IFNs) in multiple organs, including in the lung, where both stromal and hematopoietic cells showed IFN-stimulated gene (ISG) induction. Lung neutrophils expressed ISGs induced by the transcription factor IRF3, indicating an initiating role for neutrophils in this IFN response. The IFN response in Adar1(mZα/mZα) mice required the adaptor MAVS, implicating cytosolic RNA sensing. Adenosine-to-inosine changes were enriched in transposable elements and revealed a specific requirement of ADAR1’s Zα domain in editing of a subset of RNAs. Thus, endogenous RNAs in Z-conformation have immunostimulatory potential curtailed by ADAR1, with relevance to autoinflammatory disease in humans.
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spelling pubmed-84593952021-09-28 Adenosine-to-inosine editing of endogenous Z-form RNA by the deaminase ADAR1 prevents spontaneous MAVS-dependent type I interferon responses Tang, Qiannan Rigby, Rachel E. Young, George R. Hvidt, Astrid Korning Davis, Tanja Tan, Tiong Kit Bridgeman, Anne Townsend, Alain R. Kassiotis, George Rehwinkel, Jan Immunity Article Nucleic acids are powerful triggers of innate immunity and can adopt the Z-conformation, an unusual left-handed double helix. Here, we studied the biological function(s) of Z-RNA recognition by the adenosine deaminase ADAR1, mutations in which cause Aicardi-Goutières syndrome. Adar1(mZα/mZα) mice, bearing two point mutations in the Z-nucleic acid binding (Zα) domain that abolish Z-RNA binding, displayed spontaneous induction of type I interferons (IFNs) in multiple organs, including in the lung, where both stromal and hematopoietic cells showed IFN-stimulated gene (ISG) induction. Lung neutrophils expressed ISGs induced by the transcription factor IRF3, indicating an initiating role for neutrophils in this IFN response. The IFN response in Adar1(mZα/mZα) mice required the adaptor MAVS, implicating cytosolic RNA sensing. Adenosine-to-inosine changes were enriched in transposable elements and revealed a specific requirement of ADAR1’s Zα domain in editing of a subset of RNAs. Thus, endogenous RNAs in Z-conformation have immunostimulatory potential curtailed by ADAR1, with relevance to autoinflammatory disease in humans. Cell Press 2021-09-14 /pmc/articles/PMC8459395/ /pubmed/34525337 http://dx.doi.org/10.1016/j.immuni.2021.08.011 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tang, Qiannan
Rigby, Rachel E.
Young, George R.
Hvidt, Astrid Korning
Davis, Tanja
Tan, Tiong Kit
Bridgeman, Anne
Townsend, Alain R.
Kassiotis, George
Rehwinkel, Jan
Adenosine-to-inosine editing of endogenous Z-form RNA by the deaminase ADAR1 prevents spontaneous MAVS-dependent type I interferon responses
title Adenosine-to-inosine editing of endogenous Z-form RNA by the deaminase ADAR1 prevents spontaneous MAVS-dependent type I interferon responses
title_full Adenosine-to-inosine editing of endogenous Z-form RNA by the deaminase ADAR1 prevents spontaneous MAVS-dependent type I interferon responses
title_fullStr Adenosine-to-inosine editing of endogenous Z-form RNA by the deaminase ADAR1 prevents spontaneous MAVS-dependent type I interferon responses
title_full_unstemmed Adenosine-to-inosine editing of endogenous Z-form RNA by the deaminase ADAR1 prevents spontaneous MAVS-dependent type I interferon responses
title_short Adenosine-to-inosine editing of endogenous Z-form RNA by the deaminase ADAR1 prevents spontaneous MAVS-dependent type I interferon responses
title_sort adenosine-to-inosine editing of endogenous z-form rna by the deaminase adar1 prevents spontaneous mavs-dependent type i interferon responses
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459395/
https://www.ncbi.nlm.nih.gov/pubmed/34525337
http://dx.doi.org/10.1016/j.immuni.2021.08.011
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