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RNA sensing via the RIG‐I‐like receptor LGP2 is essential for the induction of a type I IFN response in ADAR1 deficiency

RNA editing by the adenosine deaminase ADAR1 prevents innate immune responses to endogenous RNAs. In ADAR1‐deficient cells, unedited self RNAs form base‐paired structures that resemble viral RNAs and inadvertently activate the cytosolic RIG‐I‐like receptor (RLR) MDA5, leading to an antiviral type I...

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Autores principales: Stok, Jorn E, Oosenbrug, Timo, ter Haar, Laurens R, Gravekamp, Dennis, Bromley, Christian P, Zelenay, Santiago, Reis e Sousa, Caetano, van der Veen, Annemarthe G
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8922249/
https://www.ncbi.nlm.nih.gov/pubmed/35156720
http://dx.doi.org/10.15252/embj.2021109760
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author Stok, Jorn E
Oosenbrug, Timo
ter Haar, Laurens R
Gravekamp, Dennis
Bromley, Christian P
Zelenay, Santiago
Reis e Sousa, Caetano
van der Veen, Annemarthe G
author_facet Stok, Jorn E
Oosenbrug, Timo
ter Haar, Laurens R
Gravekamp, Dennis
Bromley, Christian P
Zelenay, Santiago
Reis e Sousa, Caetano
van der Veen, Annemarthe G
author_sort Stok, Jorn E
collection PubMed
description RNA editing by the adenosine deaminase ADAR1 prevents innate immune responses to endogenous RNAs. In ADAR1‐deficient cells, unedited self RNAs form base‐paired structures that resemble viral RNAs and inadvertently activate the cytosolic RIG‐I‐like receptor (RLR) MDA5, leading to an antiviral type I interferon (IFN) response. Mutations in ADAR1 cause Aicardi‐Goutières Syndrome (AGS), an autoinflammatory syndrome characterized by chronic type I IFN production. Conversely, ADAR1 loss and the consequent type I IFN production restricts tumor growth and potentiates the activity of some chemotherapeutics. Here, we show that another RIG‐I‐like receptor, LGP2, also has an essential role in the induction of a type I IFN response in ADAR1‐deficient human cells. This requires the canonical function of LGP2 as an RNA sensor and facilitator of MDA5‐dependent signaling. Furthermore, we show that the sensitivity of tumor cells to ADAR1 loss requires LGP2 expression. Finally, type I IFN induction in tumor cells depleted of ADAR1 and treated with some chemotherapeutics fully depends on LGP2 expression. These findings highlight a central role for LGP2 in self RNA sensing with important clinical implications.
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spelling pubmed-89222492022-03-24 RNA sensing via the RIG‐I‐like receptor LGP2 is essential for the induction of a type I IFN response in ADAR1 deficiency Stok, Jorn E Oosenbrug, Timo ter Haar, Laurens R Gravekamp, Dennis Bromley, Christian P Zelenay, Santiago Reis e Sousa, Caetano van der Veen, Annemarthe G EMBO J Articles RNA editing by the adenosine deaminase ADAR1 prevents innate immune responses to endogenous RNAs. In ADAR1‐deficient cells, unedited self RNAs form base‐paired structures that resemble viral RNAs and inadvertently activate the cytosolic RIG‐I‐like receptor (RLR) MDA5, leading to an antiviral type I interferon (IFN) response. Mutations in ADAR1 cause Aicardi‐Goutières Syndrome (AGS), an autoinflammatory syndrome characterized by chronic type I IFN production. Conversely, ADAR1 loss and the consequent type I IFN production restricts tumor growth and potentiates the activity of some chemotherapeutics. Here, we show that another RIG‐I‐like receptor, LGP2, also has an essential role in the induction of a type I IFN response in ADAR1‐deficient human cells. This requires the canonical function of LGP2 as an RNA sensor and facilitator of MDA5‐dependent signaling. Furthermore, we show that the sensitivity of tumor cells to ADAR1 loss requires LGP2 expression. Finally, type I IFN induction in tumor cells depleted of ADAR1 and treated with some chemotherapeutics fully depends on LGP2 expression. These findings highlight a central role for LGP2 in self RNA sensing with important clinical implications. John Wiley and Sons Inc. 2022-02-14 2022-03-15 /pmc/articles/PMC8922249/ /pubmed/35156720 http://dx.doi.org/10.15252/embj.2021109760 Text en © 2022 The Authors. Published under the terms of the CC BY 4.0 license https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Stok, Jorn E
Oosenbrug, Timo
ter Haar, Laurens R
Gravekamp, Dennis
Bromley, Christian P
Zelenay, Santiago
Reis e Sousa, Caetano
van der Veen, Annemarthe G
RNA sensing via the RIG‐I‐like receptor LGP2 is essential for the induction of a type I IFN response in ADAR1 deficiency
title RNA sensing via the RIG‐I‐like receptor LGP2 is essential for the induction of a type I IFN response in ADAR1 deficiency
title_full RNA sensing via the RIG‐I‐like receptor LGP2 is essential for the induction of a type I IFN response in ADAR1 deficiency
title_fullStr RNA sensing via the RIG‐I‐like receptor LGP2 is essential for the induction of a type I IFN response in ADAR1 deficiency
title_full_unstemmed RNA sensing via the RIG‐I‐like receptor LGP2 is essential for the induction of a type I IFN response in ADAR1 deficiency
title_short RNA sensing via the RIG‐I‐like receptor LGP2 is essential for the induction of a type I IFN response in ADAR1 deficiency
title_sort rna sensing via the rig‐i‐like receptor lgp2 is essential for the induction of a type i ifn response in adar1 deficiency
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8922249/
https://www.ncbi.nlm.nih.gov/pubmed/35156720
http://dx.doi.org/10.15252/embj.2021109760
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