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RNA binding by ADAR3 inhibits adenosine-to-inosine editing and promotes expression of immune response protein MAVS

Members of the ADAR family of double-stranded RNA–binding proteins regulate one of the most abundant RNA modifications in humans, the deamination of adenosine to inosine. Several transcriptome-wide studies have been carried out to identify RNA targets of the active deaminases ADAR1 and ADAR2. Howeve...

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Autores principales: Raghava Kurup, Reshma, Oakes, Eimile K., Manning, Aidan C., Mukherjee, Priyanka, Vadlamani, Pranathi, Hundley, Heather A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9418441/
https://www.ncbi.nlm.nih.gov/pubmed/35850307
http://dx.doi.org/10.1016/j.jbc.2022.102267
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author Raghava Kurup, Reshma
Oakes, Eimile K.
Manning, Aidan C.
Mukherjee, Priyanka
Vadlamani, Pranathi
Hundley, Heather A.
author_facet Raghava Kurup, Reshma
Oakes, Eimile K.
Manning, Aidan C.
Mukherjee, Priyanka
Vadlamani, Pranathi
Hundley, Heather A.
author_sort Raghava Kurup, Reshma
collection PubMed
description Members of the ADAR family of double-stranded RNA–binding proteins regulate one of the most abundant RNA modifications in humans, the deamination of adenosine to inosine. Several transcriptome-wide studies have been carried out to identify RNA targets of the active deaminases ADAR1 and ADAR2. However, our understanding of ADAR3, the brain-specific deaminase-deficient ADAR family member, is limited to a few transcripts. In this study, we identified over 3300 transcripts bound by ADAR3 and observed that binding of ADAR3 correlated with reduced editing of over 400 sites in the glioblastoma transcriptome. We further investigated the impact of ADAR3 on gene regulation of the transcript that encodes MAVS, an essential protein in the innate immune response pathway. We observed reduced editing in the MAVS 3′ UTR in cells expressing increased ADAR3 or reduced ADAR1 suggesting ADAR3 acts as a negative regulator of ADAR1-mediated editing. While neither ADAR1 knockdown or ADAR3 overexpression affected MAVS mRNA expression, we demonstrate increased ADAR3 expression resulted in upregulation of MAVS protein expression. In addition, we created a novel genetic mutant of ADAR3 that exhibited enhanced RNA binding and MAVS upregulation compared with wildtype ADAR3. Interestingly, this ADAR3 mutant no longer repressed RNA editing, suggesting ADAR3 has a unique regulatory role beyond altering editing levels. Altogether, this study provides the first global view of ADAR3-bound RNAs in glioblastoma cells and identifies both a role for ADAR3 in repressing ADAR1-mediated editing and an RNA-binding dependent function of ADAR3 in regulating MAVS expression.
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spelling pubmed-94184412022-08-31 RNA binding by ADAR3 inhibits adenosine-to-inosine editing and promotes expression of immune response protein MAVS Raghava Kurup, Reshma Oakes, Eimile K. Manning, Aidan C. Mukherjee, Priyanka Vadlamani, Pranathi Hundley, Heather A. J Biol Chem Research Article Members of the ADAR family of double-stranded RNA–binding proteins regulate one of the most abundant RNA modifications in humans, the deamination of adenosine to inosine. Several transcriptome-wide studies have been carried out to identify RNA targets of the active deaminases ADAR1 and ADAR2. However, our understanding of ADAR3, the brain-specific deaminase-deficient ADAR family member, is limited to a few transcripts. In this study, we identified over 3300 transcripts bound by ADAR3 and observed that binding of ADAR3 correlated with reduced editing of over 400 sites in the glioblastoma transcriptome. We further investigated the impact of ADAR3 on gene regulation of the transcript that encodes MAVS, an essential protein in the innate immune response pathway. We observed reduced editing in the MAVS 3′ UTR in cells expressing increased ADAR3 or reduced ADAR1 suggesting ADAR3 acts as a negative regulator of ADAR1-mediated editing. While neither ADAR1 knockdown or ADAR3 overexpression affected MAVS mRNA expression, we demonstrate increased ADAR3 expression resulted in upregulation of MAVS protein expression. In addition, we created a novel genetic mutant of ADAR3 that exhibited enhanced RNA binding and MAVS upregulation compared with wildtype ADAR3. Interestingly, this ADAR3 mutant no longer repressed RNA editing, suggesting ADAR3 has a unique regulatory role beyond altering editing levels. Altogether, this study provides the first global view of ADAR3-bound RNAs in glioblastoma cells and identifies both a role for ADAR3 in repressing ADAR1-mediated editing and an RNA-binding dependent function of ADAR3 in regulating MAVS expression. American Society for Biochemistry and Molecular Biology 2022-07-15 /pmc/articles/PMC9418441/ /pubmed/35850307 http://dx.doi.org/10.1016/j.jbc.2022.102267 Text en © 2022 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 Research Article
Raghava Kurup, Reshma
Oakes, Eimile K.
Manning, Aidan C.
Mukherjee, Priyanka
Vadlamani, Pranathi
Hundley, Heather A.
RNA binding by ADAR3 inhibits adenosine-to-inosine editing and promotes expression of immune response protein MAVS
title RNA binding by ADAR3 inhibits adenosine-to-inosine editing and promotes expression of immune response protein MAVS
title_full RNA binding by ADAR3 inhibits adenosine-to-inosine editing and promotes expression of immune response protein MAVS
title_fullStr RNA binding by ADAR3 inhibits adenosine-to-inosine editing and promotes expression of immune response protein MAVS
title_full_unstemmed RNA binding by ADAR3 inhibits adenosine-to-inosine editing and promotes expression of immune response protein MAVS
title_short RNA binding by ADAR3 inhibits adenosine-to-inosine editing and promotes expression of immune response protein MAVS
title_sort rna binding by adar3 inhibits adenosine-to-inosine editing and promotes expression of immune response protein mavs
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9418441/
https://www.ncbi.nlm.nih.gov/pubmed/35850307
http://dx.doi.org/10.1016/j.jbc.2022.102267
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